REVIEW
published: 12 August 2021
Edited by:
Michał Tomczyk,
Medical University of Bialystok, Poland
Reviewed by:
Ulrike Lindequist,
University of Greifswald, Germany
Armando Caceres,
Universidad de San Carlos de
Guatemala, Guatemala
*Correspondence:
Xirui He
xiruihe6105194@163.com
Nan Zeng
19932015@cdutcm.edu.cn
†
These authors have contributed
equally to this work
Specialty section:
This article was submitted to
Ethnopharmacology,
a section of the journal
Frontiers in Pharmacology
Received: 24 April 2021
Accepted: 02 July 2021
Published: 12 August 2021
Citation:
Luan F, Peng L, Lei Z, Jia X, Zou J,
Yang Y, He X and Zeng N (2021)
Traditional Uses, Phytochemical
Constituents and Pharmacological
Properties of Averrhoa carambola L.:
A Review.
Front. Pharmacol. 12:699899.
doi: 10.3389/fphar.2021.699899
Frontiers in Pharmacology | www.frontiersin.org
doi: 10.3389/fphar.2021.699899
Traditional Uses, Phytochemical
Constituents and Pharmacological
Properties of Averrhoa carambola L.: A
Review
Fei Luan 1†, Lixia Peng 1†, Ziqin Lei 1, Xiyu Jia 1, Junbo Zou 2, Yan Yang 3, Xirui He 3* and
Nan Zeng 1*
1
State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional
Chinese Medicine, Chengdu, China, 2Department of Pharmacology, College of Pharmacy, Shaanxi University of Chinese
Medicine, Xianyang, China, 3Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai, China
Averrhoa carambola L. (star fruit) is an edible fruit that is extensively cultivated in
southern China, Southeast Asia, India, and northern South America. It has a sweet
and juicy taste and is frequently used in fruit salads and fruit platters, as a garnish in
cocktail drinks and beverages, or squeezed into juice and served as a beverage.
Traditionally, it has been used for treating diabetes and diabetic nephropathy,
arthralgia, vomiting, lithangiuria, coughing, hangovers, and chronic paroxysmal
headache for thousands of years. Currently, approximately 132 compounds have
been isolated from A. carambola. Among them, flavonoids, benzoquinone, and their
glycosides have been considered as biologically active substances, which are
responsible for various biological activities. Pharmacological studies have
revealed that crude extracts or monomeric compounds from A. carambola
exhibit multiple bioactivities, such as anti-oxidant, anti-hyperglycemic, anti-
obesity, anti-hyperlipidemic, anti-tumor, anti-inflammatory, hepatoprotective,
cardioprotective, anti-hypertensive, neuroprotective, and others. Thus, A.
carambola is a valuable treatment in Chinese medicine with therapeutic potential
for multiple diseases, especially diabetes and diabetes-related diseases. Even
though it is a very promising candidate in the development of functional food
and the pharmaceutical industry, reports on its bioactivities have only been
conducted in vivo and in vitro and there is a gap in research regarding clinical
settings and safety. This review therefore provides a comprehensive and systematic
overview of current progress on botany, ethnopharmacology, phytochemistry,
pharmacology, and toxicity of A. carambola, providing a valuable reference for
further developments and applications of A. carambola in the pharmaceutical
industry and functional food.
Keywords: Averrhoa carambola, chemical composition, antidiabetic, anticancer, toxicology
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Luan et al. Phytochemistry and Pharmacology of Averrhoa carambola

INTRODUCTION cultivated throughout tropical and warm subtropical areas

Averrhoa carambola L., commonly known as carambola or star
fruit, is a perennial tree in the family Oxalidaceae (Figure 1). It is
considered native to Malaysia, however, it is a tropical American
species introduced to Asia by the Spanish galleons and mainly
(Figure 2). The fruit is of high commercial value and is
specially and extensively distributed and cultivated in southern
China, Southeast Asia, India, and northern South America (Saikia
et al., 2015; Leivas et al., 2016b; Varela-Martínez et al., 2019;
Zulfajri et al., 2019). A. carambola is fleshy, crunchy, juicy,

FIGURE 1 | A. carambola: (A): whole plants; (B): fruits; (C): flowers and woods; (D): leaves (https://image.baidu.com/).

FIGURE 2 | Geographical distribution of A. carambola throughout the world (https://www.cabi.org/isc/datasheet/8082).

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Luan et al.
slightly tart, acidic, and sweet in the taste. It is star-shaped and
golden-yellow in appearance and is frequently used in the
preparation of fruit salads and fruit platters, as a garnish in
cocktails and beverages, or squeezed into a juice and served as a
functional beverage. It is also used in jellies, ice creams, preserves,
and sweets owing to its high moisture content and highly
perishability, especially in tropical regions such as Malaysia,
Singapore, and Indonesia (Valim et al., 2016; Chua et al.,
2017; Huynh and Nguyen, 2017; Jia et al., 2018; Lu et al.,
2018). For instance, in Malaysia star fruits are usually blended
with apples and braised with cloves and sugars or cooked along
with meat or seafood (Bhat et al., 2011). Generally, star fruits are
regarded as an abundant source of various nutrients such as
minerals, proteins, and vitamins, and also rich in natural
phytochemicals such as flavonoids, terpenes, saponins,
alkaloids, proanthocyanidins, vitamin C, tartaric acid, oxalic
acid, α-ketoglutaric acid, citric acid, vitamin B1 and B2,
carotene, pectin, cellulose, gallic acid, epicatechin, fatty acids,
volatile flavors, fibers, hemicellulose, polysaccharides, and sterols
(Shui and Leong, 2006; Benkeblia and Lopez, 2015; Leivas et al.,
2015; Muthu et al., 2016; Yang et al., 2017; Zulfajri et al., 2019).
Simultaneously, GC-MS analysis has demonstrated that the
abundant fatty acids existing in A. carambola leaves were
α-linolenic acid (62.04%) and oleic acid (55.44%) in fruits.
Moreover, the proportion of total unsaturated fatty acids
existing both in the fruits and leaves of A. carambola comprise
more than 77% of total fatty acid (Wei et al., 2014). The fructose
content (38–48%) and glucose content (21–25%) have
predominantly sugar-based compositions in A. carambola ripe
fruits, while sorbitol is also another major sugar alcohol
(2.4–10.5%) in ripe fruits (Ramadan et al., 2020). Additionally,
the presence of high amounts of fibers in this plant contributes to
the absorption of glucose, restraint glucose diffusion into the
bloodstream, and maintain normal blood glucose levels (Fan
et al., 2020). Furthermore, the byproduct or pomace residue
from A. carambola left after juice drink extraction contains
more antioxidants than the extracted juice (Shui and Leong,
2006). Interestingly, incorporation of 4% A. carambola fruit
juice and 6% Bambusa polymorpha Munro (Poaceae family)
shoot extract, significantly prolonged the shelf life of pork
nuggets by at least 2 weeks (Thomas et al., 2016). Recent
studies found that an antifreeze protein purified from the cold
acclimated leaves of Drimys angustifolia Miers (Winteraceae
family) and synergistic pectin-maltodextrin-sodium chloride
edible coating could dramatically increase the quality of frozen
A. carambola (Provesi et al., 2019; Mohd Suhaimi et al., 2021).
In recent years, phytochemical investigations have revealed
that the major chemical components of A. carambola mainly
include flavonoids, terpenes, and other phenolics. Among them,
2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (122,
DMDD) is the most representative chemical compound with
multiple biological activities (Gao et al., 2015; Xie et al., 2016;
Chen et al., 2017b). Pharmacological studies have demonstrated
that the crude extracts or active substances of A. carambola have
multiple health-promoting effects, and many of the biological
effects above mentioned have ethnomedicinal uses. Furthermore,
the usable range of A. carambola is increasingly expanding from
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Phytochemistry and Pharmacology of Averrhoa carambola
medicinal plants to ornamental plants in gardens. For instance, A.
carambola is widely planted as a decorative tree in the streets of
southern Chinese cities because of its beautiful appearance (Wu
et al., 2020b). More importantly, it is reported that the total
consumption per year of A. carambola in China is about 2.6
million tons, whereas the annual production of A. carambola is
only two million tons (Wu et al., 2020b).
To date, there has been no authoritative published systematic
and comprehensive review that focuses on all of the important
aspects of A. carambola. In the present review, recent advances in
traditional uses, botanical characteristics, distribution, taxonomy,
phytochemical constituents, biological effects as well as the
toxicities of A. carambola are comprehensively presented and
critically evaluated. Furthermore, the underlying mechanism
associated with the bioactivities of crude extracts or
components from this plant is also well summarized. The
review is helpful for researchers by providing a comprehensive
understanding of this increasingly important herb and provides a
scientific basis for further study and exploitation of medicinal
agents or functional food from A. carambola in the future.
MATERIAL AND METHODS
This review collected, analyzed, summarized literature on the
botanical description, traditional uses, chemical constituents,
pharmacological activities, and toxicities of A. carambola. All
information was systematically gathered from globally accepted
scientific databases by Internet databases, including Elsevier,
ScienceDirect, PubMed, Web of Science, Wiley, Springer,
SciFinder, ACS Publications, CNKI, WanFang, Google Scholar,
Baidu Scholar, The Plant List Database, and other literature
sources (Ph.D. and MSc dissertations). All published
contributions on A. carambola in different languages were
included and cited. The identification and examination of the
collected works were based on titles and abstracts. The reference
lists of the retrieved publications were also checked to identify
further relevant papers. The chemical structures of all isolated
compounds were drawn by using ChemBioDraw Ultra 14.0
software.
BOTANICAL DESCRIPTION, GEOGRAPHIC
DISTRIBUTION, AND TAXONOMY
Botanical Description
Botanically, A. carambola is a medium-sized tree reaching up to
3–15 m tall. The stem is gray bark. The leaf is odd-numbered
compound leaves, alternate, leaflets 5-13, entire, ovoid, or elliptic,
3–7 cm long, acuminate at apex, with a round base, skewed on
one side, sparsely pilose or glabrous underneath. The flower is
cymes or panicles; sepals 5, about 5 mm long, arranged in
imbricate shape, synthetic ring at the base; petals slightly
dorsal, 0.8–1 cm long, purple-red, sometimes pink or white on
the back; stamens 5-10; Ovary 5 compartments, many ovules in
each compartment, style 5. The fruit is fleshy, drooping, with 5
edges, rarely 6 or 3 edges, star-shaped in cross section, 5–8 cm
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Luan et al.
long, light green or waxy yellow, sometimes dark red. The seed is
dark brown (Flora of China Editorial Committee, 1998).
Geographic Distribution
A. carambola is traditionally considered to originate from
Malaysia, although it has also been speculated to be a
tropical American species introduced to Asia by the Spanish
galleons. A. carambola has a wider climate range and can grow
within the latitudinal range from 32°N to 30°S and withstand
growing in both the hot humid tropics and subtropical
countries including Egypt and Israel, and can tolerate short
periods of freezing temperatures as low as −3°C. It prefers well-
drained soils ideally between pH 5.5–6.5 but can tolerate pH
between 5 and 8.5 (Bircher and Bircher, 2000). In recent years,
it has been extensively distributed and widely cultivated in
most parts of the world (Figure 2), e.g., Asia countries
including China and India, Africa countries including
Madagascar and Tanzania, North America countries
including Mexico and Honduras, Oceania countries
including Australia and French Polynesia, South America
countries including Brazil and Bolivia, etc. (https://www.
cabi.org/isc/datasheet/8082).
Taxonomy
A. carambola belongs to the family Oxalidaceae, which
consists of over 900 species belonging to seven genera, such
as Dapania, Oxalis, Sarcotheca, Eichleria, Biophytum,
Hypseocharis, and Averrhoa. Among them, the genus
Averrhoa mainly includes three species, namely A.
carambola, A. bilimbi L., and A. dolichocarpa Ruhayah and
Sunart (https://www.cabi.org/isc/datasheet/8082; Moresco
et al., 2012). Importantly, A. carambola is commonly
known as star fruit or carambola, bearing deeply ridged,
yellow-brown, edible fruit.
TRADITIONAL USES
A. carambola has been traditionally used for thousands of
years in treating diabetes and diabetic nephropathy (DN),
arthralgia, vomiting, lithangiuria, coughing and hangovers,
and chronic paroxysmal headache. The different medicinal
organs of A. carambola including leaves, roots, flowers, and
the fruits have been utilized as ethnomedicine in Chinese,
Indian, Malaysian, and Brazilian medicine for a long time. For
instance, the crushed shoots or leaves of A. carambola are
commonly applied in traditional Malaysia medicine to treat
headache, chicken-pox, and ringworm, while a decoction of
the leaves and fruits of A. carambola is generally used for
treating vomiting, fevers, aphthous stomatitis, and angina
(Yang et al., 2020b). In Sri Lanka, A. carambola fruits are
traditionally used to treat and prevent diabetes mellitus due to
their excellent hypoglycemic effects (Abeysekera et al., 2015).
In traditional Brazilian medicine, the fruit, juice, as well as tea
made from leaves of A. carambola have been traditionally
utilized to prevent and treat diabetes, high blood pressure, and
urinary system diseases and A. carambola is also considered as
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Phytochemistry and Pharmacology of Averrhoa carambola
a food supplement that can improve the appetite of people
with poor appetite (Vasconcelos et al., 2006; Soncini et al.,
2011). The traditional Indian medicine records that the ripe
fruits of A. carambola can be used for effectively curing the
hemorrhage of hemorrhoids and it is also regarded as a
remedy for the treatment of eczema, fever, and diarrhea.
Furthermore, the ripe fruit of A. carambola is mainly
considered as digestive and tonic in Ayurveda (Vasant and
Narasimhacharya, 2014). As a Traditional Chinese Medicine
(TCM), the roots, fruits, and leaves of A. carambola have been
increasingly recognized as an effective herbal medicine in
invigorating kidney function and reinforcing Yang (it refers to
the masculine, active and positive principle) and is used for
the treatment of various ailments with a long history (World
Health Organization and Regional Office for the Western
Pacific, 2007; Wei et al., 2018). More specifically, the roots
of A. carambola have been commonly accepted as a diuretic
and appetite stimulant agent, it is also used as an antidiarrheal
and febrifugal drug with a long history of medical use in TCM
for the treatment of arthralgia, diabetes, DN, lithangiuria, and
chronic paroxysmal headache in ancient times (Cabrini et al.,
2011; Wen et al., 2013; Zheng et al., 2013; Chen et al., 2017b).
At the same time, A. carambola leaves have been commonly
utilized for alleviating vomiting, headaches, diabetes,
coughing, and hangovers for a many years (Carolino et al.,
2005; Ferreira et al., 2008). Furthermore, A. carambola fruits
are frequently applied to effectively remedy malarial
splenomegaly and food poisoning caused by meat sources
(Pang et al., 2017). Overall, the leaves, roots, flowers, and
fruits of this plant, might be used as a dietary supplement and
should be further studied and developed as a functional food
or therapeutic agent in the management of human health.
NUTRITIONAL AND PHYTOCHEMICAL
COMPOSITION
Nutritional Composition
Nutrient substances, such as minerals, vitamins, cellulose,
hemicelluloses, pectin, and others are contained in the fruit
of A. carambola. It has been reported that A. carambola
contains cellulose (60%), hemicelluloses (27%), and pectin
(13%), which may contribute to controlling blood sugar
levels (Lakmal et al., 2021). Moreover, carotene, vitamins,
and acids were found in the ripe fruit of A. carambola, with
high levels of vitamin C (25.8 mg/100 g fruit), tartaric acid
(4.37 mg/100 g fruit), vitamin B1 and B2 (0.12 mg/100 g fruit)
(Muthu et al., 2016). Furthermore, mineral elements were also
found to be contained in A. carambola, with high levels of
potassium (167.13–168.0 mg/100 g fruit), phosphorous
(17.87–17.88 mg/100 g fruit), magnesium (11.85–12.05 mg/
100 g fruit), calcium (6.37–6.40 mg/100 g fruit), sodium
(3.8–3.85 mg/100 g fruit), iron (0.34–0.45 mg/100 g fruit),
zinc (0.29–0.51 mg/100 g fruit), copper (0.19–0.45 mg/100 g
fruit), and manganese (0.04–0.52 mg/100 g fruit) (Muthu et al.,
2016). These results indicate that A. carambola is low-calorie
and may also have health-promoting properties.
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Luan et al. Phytochemistry and Pharmacology of Averrhoa carambola

TABLE 1 | Chemical components isolated and structurally identified from A. carambola.

No. Chemical constituents Molecular Extracts Parts References

formula

Flavonoids
1 Carambolaside R1 C35H38O14 EtOH Leaves Yang et al. (2020a)
2 Carambolaside R2 C35H38O14 EtOH Leaves Yang et al. (2020a)
3 Carambolaside R3 C35H38O15 EtOH Leaves Yang et al. (2020a)
4 Carambolaside S1 C41H48O18 EtOH Leaves Yang et al. (2020a)
5 Carambolaside S2 C41H48O18 EtOH Leaves Yang et al. (2020a)
6 Carambolaside T1 C41H48O18 EtOH Leaves Yang et al. (2020a)
7 Carambolaside T2 C41H48O18 EtOH Leaves Yang et al. (2020a)
8 Carambolaside T3 C41H48O19 EtOH Leaves Yang et al. (2020a)
9 3-Hydroxycarambolaside T1 C41H48O19 EtOH Leaves Yang et al. (2020a)
10 3-Hydroxycarambolaside P C47H58O24 EtOH Leaves Yang et al. (2020a)
11 Carambolaside M C32H42O18 EtOH Fruits Jia et al. (2018)
12 Carambolaside N C38H52O22 EtOH Fruits Jia et al. (2018)
13 Carambolaside O C47H58O23 EtOH Fruits Jia et al. (2018)
14 Carambolaside P C47H58O23 EtOH Fruits Jia et al. (2018)
15 Carambolaside Q C41H48O19 EtOH Fruits Jia et al. (2018)
16 Carambolaside A C21H24O9 MeOH Fruits Yang et al. (2015)
17 Carambolaside B C30H30O10 MeOH Fruits Yang et al. (2015)
18 Carambolaside C C27H34O14 MeOH Fruits Yang et al. (2015)
19 Carambolaside D C36H40O15 MeOH Fruits Yang et al. (2015)
20 Carambolaside E C27H34O13 MeOH Fruits Yang et al. (2016)
21 Carambolaside F C36H40O14 MeOH Fruits Yang et al. (2016)
22 Carambolaside G C36H40O14 MeOH Fruits Yang et al. (2016)
23 Carambolaside H C36H40O15 MeOH Fruits Yang et al. (2016)
24 Carambolaside I C41H48O18 MeOH Fruits Yang et al. (2016)
25 Carambolaside Ia C41H48O18 MeOH Fruits Yang et al. (2016)
26 Carambolaside J C47H58O22 MeOH Fruits Yang et al. (2016)
27 Carambolaside Ja C47H58O22 MeOH Fruits Yang et al. (2016)
28 8-carboxymethyl-(+)-epicatechin methyl ester C18H18O8 EtOH Fruits Jia et al. (2018)
29 (+)-Epicatechin C15H14O6 EtOH Fruits Jia et al. (2018)
30 Epicatechin-(5,6-bc)-4β-(p-hydroxyphenyl)-dihydro-2(3H)-pyranone C24H20O8 EtOH Leaves Yang et al. (2020b)
31 Epicatechin-(7,8-bc)-4α-(p-hydroxyphenyl)-dihydro-2(3H)-pyranone C24H20O8 EtOH Leaves Yang et al. (2020b)
32 Epicatechin-(7,8-bc)-4β-(p-hydroxyphenyl)-dihydro-2(3H)-pyranone C24H20O8 EtOH Leaves Yang et al. (2020b)
33 6-(S-2-Pyrrolidinone-5-yl)-epicatechin C19H19NO7 EtOH Leaves Yang et al. (2020b)
34 6-(R-2-pyrrolidinone-5-yl)-epicatechin C19H19NO7 EtOH Leaves Yang et al. (2020b)
35 (–)-Epicatechin C15H14O6 EtOAc Fruits Gunawardena et al. (2015)
36 Pinobanksin 3-O-β-D-glucoside C21H22O10 EtOH Fruits Jia et al. (2018)
37 Aromadendrin 3-O-β-D-glucoside C21H22O11 EtOH Fruits Jia et al. (2018)
38 Helicioside A C21H22O12 EtOH Fruits Jia et al. (2018)
39 Taxifolin 3′-O-β-D-glucoside C21H22O12 EtOH Fruits Jia et al. (2018)
40 Norathyriol C13H8O6 EtOH Fruits Jia et al. (2018)
41 Isorhamnetin 3-O-rutinoside C28H32O16 EtOH Fruits Jia et al. (2018)
42 Hovertichoside C C36H46O14 MeOH Fruits Yang et al. (2015)
43 Isovitexin 2″-O-α-L-rhamnopyranoside C27H30O14 MeOH Fruits Yang et al. (2015)
44 Carambolaflavone C27H30O13 MeOH Fruits Yang et al. (2015)
45 (+)-Catechin C15H14O6 Aqueous Roots Liao et al. (2019a)
46 Isovitexin C21H22O10 EtOH Leaves Araho et al. (2005)
47 Carambolaflavone A C27H30O13 EtOH Leaves Araho et al. (2005), Moresco et al. (2012),
Wang et al. (2018)
48 Carambolaflavone B C27H30O13 EtOH Leaves Araho et al. (2005), Moresco et al. (2012),
Wang et al. (2018)
49 Apigenin 6-C-(2′′-O-α-L-rhamnopyranosyl)-β-D-glucopyranoside C36H37O18 EtOH Leaves Moresco et al. (2012)
50 Cyanidin-3-O-β-D-glucoside C21H21O11Cl EtOH Leaves Gunasegaran (1992)
51 Cyanidin-3, 5-O-β-D-diglucoside C27H37O16Cl EtOH Leaves Gunasegaran (1992)
Terpenes
52 (5R,6S,7E,9R)-5,6,9-trihydroxy-7-megastigmene 9-O-β-D-glucoside C19H34O8 EtOH Fruits Jia et al. (2019)
53 Drovomifoliol C13H19O3 EtOH Fruits Jia et al. (2019)
54 3-oxo-α-ionol-9-O-β-D-glucoside C19H31O7 EtOH Fruits Jia et al. (2019)
55 Roseoside C19H30O8 EtOH Fruits Jia et al. (2019)
56 3-oxo-9-O-β-D-glucosyloxy-4,6E-megastigmadien C19H30O8 EtOH Fruits Jia et al. (2019)
57 4-oxo-β-ionol 9-O-β-D-glucoside C19H31O8 EtOH Fruits Jia et al. (2019)
58 Cannabiside D C19H30O9 EtOH Fruits Jia et al. (2019)
59 Dendranthemoside B C19H32O8 EtOH Fruits Jia et al. (2019)
(Continued on following page)

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TABLE 1 | (Continued) Chemical components isolated and structurally identified from A. carambola.

No. Chemical constituents Molecular Extracts Parts References

formula

60 Icariside C27H30O11 EtOH Fruits Jia et al. (2019)

61 Officinoside A C19H32O8 EtOH Fruits Jia et al. (2019)
62 6S,7E,10S)-△9,15-10-hydroxyabscisic alcohol C15H22O4 EtOH Fruits Jia et al. (2019)
63 Abscisic acid C15H20O4 EtOH Fruits Jia et al. (2019)
64 Abscisyl β-D-glucoside C21H31O10 EtOH Fruits Jia et al. (2019)
65 9E-abscisic acid C15H20O4 EtOH Fruits Jia et al. (2019)
66 9E-abscisyl β-D-glucoside C21H32O10 EtOH Fruits Jia et al. (2019)
67 9E-abscisic alcohol β-D-glucoside C21H33O9 EtOH Fruits Jia et al. (2019)
68 cis-abscisic acid C15H20O4 EtOAc Fruits Gunawardena et al. (2015)
69 trans-abscisic acid C15H20O4 EtOAc Fruits Gunawardena et al. (2015)
70 trans-abscisic alcohol C15H22O3 EtOAc Fruits Gunawardena et al. (2015)
71 (6S,9R)-vomifoliol C13H20O3 EtOAc Fruits Gunawardena et al. (2015)
72 cis-abscisic acid β-D-glucopyranosyl ester C22H32O8 EtOAc Fruits Gunawardena et al. (2015)
73 trans-abscisic alcohol β-D-glucopyranoside C22H33O7 EtOAc Fruits Gunawardena et al. (2015)
74 (6S,9R)-roseoside C14H22O3 EtOAc Fruits Gunawardena et al. (2015)
75 cis-abscisic alcohol β-D-glucopyranoside C22H33O7 EtOAc Fruits Gunawardena et al. (2015)
76 Artemisinic acid C15H22O2 EtOH Fruits Yang et al. (2012)
77 3-β-hydroxyartemisinic acid C15H22O3 EtOH Fruits Yang et al. (2012)
78 Artemisinic acid 3-β-O-β-D-glucopyranoside C21H32O8 EtOH Fruits Yang et al. (2012)
79 3-β-hydroxyartemisinic acid β-D-glucopyranosyl ester C21H32O8 EtOH Fruits Yang et al. (2012)
80 Arjunolic acid C30H48O5 MeOH Fruits Yang et al. (2014)
Phenolics
81 Vanillic acid C 8H 8O4 MeOH Fruits Yang et al. (2014)
82 8,9,10-trihydroxythymol C10H10O4 MeOH Fruits Yang et al. (2014)
83 Carambolaside K C30H48O15 EtOH Fruits Jia et al. (2017)
84 Carambolaside L C32H52O16 EtOH Fruits Jia et al. (2017)
85 Koaburaside C14H20O9 EtOH Fruits Jia et al. (2017)
86 3,4,5-trimethoxyphenol-1-O-β-D-glucopyranoside C15H22O9 BuOH Roots Wen et al. (2012)
87 3,5-dimethoxy-4-hydroxyphenyl 1-O-β-apiofuranosyl (1’’→6’)-O-β-D- C19H28O13 BuOH Roots Wen et al. (2012)
glucopyranoside
88 3,4,5-trimethoxyphenyl 1-O-β-apiofuranosyl (1’’→6’)-β-glucopyranoside C20H30O13 BuOH Roots Wen et al. (2012)
89 Methoxyhydroquinone-4-β-D-glucopyranoside C13H18O18 BuOH Roots Wen et al. (2012)
90 3-hydroxy-4-methoxyphenol 1-O-β-D-apiofuranosyl-(1’’→6’)-O-β-D- C18H26O12 BuOH Roots Wen et al. (2012)
glucopyranoside
91 4-hydroxy-3-methoxyphenol 1-O-β-D-apiofuranosyl-(1’’→6’)-O-β-D- C18H26O12 BuOH Roots Wen et al. (2012)
glucopyranoside
92 Protocatechuic acid C 7H 6O4 EtOH Fruits Jia et al. (2017)
93 1-O-vanilloyl-β-D-glucose C14H18O9 EtOH Fruits Jia et al. (2017)
94 2,5-dimethoxy-3-undecylphenol C19H33O3 EtOAc Wood Chakthong et al. (2010)
95 5-methoxy-3-undecylphenol C18H31O2 EtOAc Wood Chakthong et al. (2010)
96 Gallic acid C 7H 6O5 Acetone Fruits Shui and Leong (2004)
Phenylpropanoids
97 Ferulic acid C10H10O4 MeOH Fruits Yang et al. (2014)
98 (+)-isolariciresinol 9-O-β-D-glucoside C27H36O12 EtOH Fruits Jia et al. (2017)
99 (+)-lyoniresinol 9-O-β-D-glucoside C28H38O13 EtOH Fruits Jia et al. (2017)
100 (−)-lyoniresinol 9-O-β-D-glucoside C28H38O13 EtOH Fruits Jia et al. (2017)
101 1-O-feruloyl-β-D-glucose C16H20O9 EtOH Fruits Jia et al. (2017)
102 Tarennanosides A C37H46O17 Aqueous Roots Liao et al. (2019a)
103 Fernandoside C36H44O16 Aqueous Roots Liao et al. (2019a)
104 7α-[(β-glucopyranosyl) oxy]-lyoniresinol C28H38O13 Aqueous Roots Liao et al. (2019a)
105 (+)-lyoniresinol 3α-O-β-D-glucopyranoside C28H38O13 Aqueous Roots Liao et al. (2019a)
106 (−)-lyoniresinol 3α-O-β-D-glucopyranoside C28H38O13 Aqueous Roots Liao et al. (2019a)
107 (−)-5′-methoxy-isolariciresinol 3α-O-β-D-glucopyranoside C27H36O12 Aqueous Roots Liao et al. (2019a)
108 (+)-5′-methoxy-isolariciresinol 3α-O-β-D-glucopyranoside C27H36O12 BuOH Roots Wen et al. (2012)
109 (+)-isolariciresinol 3α-O-β-D-glucopyranoside C26H34O11 BuOH Roots Wen et al. (2012)
110 (−)-isolariciresinol 3α-O-β-D-glucopyranoside C26H34O11 BuOH Roots Wen et al. (2012)
111 Reticulol C11H10O5 EtOAc Fruits Sritharan et al. (2019)
112 6-O-methyl-reticulol C11H10O5 EtOAc Fruits Sritharan et al. (2019)
113 5-methylmellein C11H12O3 EtOAc Fruits Sritharan et al. (2019)
114 7-hydroxy-5-methylmellein C11H12O4 EtOAc Fruits Sritharan et al. (2019)
Other constituents
115 Benzyl-1-O-β-D-glucopyranoside C13H18O6 BuOH Roots Wen et al. (2012)
116 (2S)-2-O-β-D-glucopyranosyl-2-hydroxyphenyl-acetic acid C14H18O8 BuOH Roots Wen et al. (2012)
(Continued on following page)

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Luan et al. Phytochemistry and Pharmacology of Averrhoa carambola

TABLE 1 | (Continued) Chemical components isolated and structurally identified from A. carambola.

No. Chemical constituents Molecular Extracts Parts References

formula

117 Methyl 2-β-D-apiofuranosyl-(1→6)-β-D-glucopyranosyloxybenzoate C19H26O12 EtOH Leaves Yang et al. (2020b)

118 Benzyl 2-β-D-apiofuranosyl-(1→6)-β-D-glucopyranosyloxybenzoate C25H30O12 EtOH Leaves Yang et al. (2020b)
119 Tecomin C15H20O9 EtOH Fruits Jia et al. (2017)
120 L-ascorbic acid C 6H 8O6 Acetone Fruits Shui and Leong (2004)
121 2-methoxy-6-nonyl-cyclohexa-2,5-diene-1,4-dione C16H24O3 EtOH Roots Wen et al. (2014)
122 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione C19H30O3 EtOH Roots Zhang et al. (2020)
123 5-O-methylembelin C18H28O4 EtOAc Woods Chakthong et al. (2010)
124 2-dehydroxy-5-O-methylembelin C18H28O3 EtOAc Woods Chakthong et al. (2010)
125 (+)-cryptosporin C14H12O6 EtOH Fruits Jia et al. (2017)
126 (1R*,3S*)-1-(5-hydroxymethylfuran-2-yl)-3-carboxy-6-hydroxy-8- C16H17NO6 MeOH Fruits Yang et al. (2014)
methoxyl-1,2,3,4-tetrahydroisoquinoline
127 (1S*,3S*)-1-methyl-3-carboxy-6-hydroxy-8-methyoxyl-1,2,3,4- C12H15NO4 MeOH Fruits Yang et al. (2014)
tetrahydroisoquinoline
128 Heptyl vicianoside C18H34O10 EtOH Fruits Yang et al. (2019b)
129 Octyl vicianoside C21H30O11 EtOH Fruits Yang et al. (2019b)
130 cis-3-hexenyl rutinoside C34H43O16 EtOH Fruits Yang et al. (2019b)
131 Methyl 2-O-β-D-fucopyranosyl-α-L-arabinofuranoside C12H22O9 EtOH Fruits Yang et al. (2019b)
132 Methyl α-D-fructofuranoside C7H14O6 EtOH Fruits Yang et al. (2019b)

EtOH, ethanol; EtOAc, ethyl acetate; n-BuOH, n-butanol.

Phytochemical Compounds Terpenes

Currently, approximately 132 phytochemical compounds have
been separated and identified from A. carambola, which contains
flavonoids, terpenes, phenylpropanoids, and their glycosides,
among others. These include flavonoids, benzoquinone and
their glycosides, which have been considered as the
biologically active components responsible for multiple
bioactivities. The compounds isolated from A. carambola are
documented and listed in Table 1 and the chemical structures are
drawn and presented in Figure 3.
Flavonoids
Various studies have found that the flavonoids isolated from this
plant possess excellent antioxidant and radical scavenging
properties, which can be used to prevent and treat the
occurrence of chronic and cardiovascular illness (Maqsood
et al., 2020). Until now, 51 flavonoids (1–51) have been
separated and characterized by nuclear magnetic resonance
(NMR) and mass spectrometer (MS) technologies from the
leaves, fruits, and roots of A. carambola. Among these are
compounds (1–27) that are dihydrochalcone C-glycosides and
other compounds (28–35) are flavan-3-ols, of which all exhibited
significant radical scavenging activities against the DPPH and
ABTS, while some compounds (36–51) are other types with
multiple structures. Both the compounds carambolaflavone A
(47) and carambolaflavone B (48) showed excellent
antihyperglycemic activity both in hyperglycemic and diabetic
rats’ model (Cazarolli et al., 2009; Cazarolli et al., 2012).
Afterward, Wang et al. (2018) conducted the total synthesis of
the enantiomers of carambolaflavone A (47) and found that
structurally the β-fucosyl moiety absolute configuration was D
instead of L. Information of these isolated flavonoids is listed in
Table 1. Their chemical structures were drawn by ChemBioDraw
Ultra 14.0 and are described in Figure 3.
Terpenes are a group of secondary metabolites in plants that
consist of one or more isoprene subunits (Bahramsoltani et al.,
2020). They have the function of promoting the coloring in many
and various vegetables and fruits (Farias et al., 2020). To date, 29
terpenes (52–80) have been mainly separated and identified from
the fresh fruits of A. carambola. Gunawardena et al. (2015)
analyzed different terpenes in star fruits using NMR and MS
methods, and the major terpenes identified were cis-abscisic acid
(68, 12 mg), trans-abscisic acid (69, 3.5 mg), trans-abscisic
alcohol (70, 12 mg), (6S,9R)-vomifoliol (71, 8.5 mg), cis-
abscisic acid β-D-glucopyranosyl ester (72, 19 mg), trans-
abscisic alcohol β-D-glucopyranoside (73, 12 mg), (6S,9R)-
roseoside (74, 12 mg), and cis-abscisic alcohol β-D-
glucopyranoside (75, 113 mg). Moreover, Jia et al. (2019)
found that the terpenes-derived components from star fruits
are primarily C13- and C15-norisoprenoids, which
tremendously strengthen the flavor of A. carambola fruits.
Information of these terpenes is listed in Table 1. The
chemical structures were draw by ChemBioDraw Ultra 14.0
and are shown in Figure 3. However, the pharmacological
activities of most terpenes is still unclear.
Phenolics
Phenolic compositions are represented as one of the major classes
of plant secondary metabolites and extensively dispersed among
plant parts, phytochemical studies have found that these
compounds principally exist in the roots and fruits of A.
carambola (Wen et al., 2012; Yang et al., 2014; Jia et al., 2017;
Liao et al., 2019a). At present, 16 phenolic components (81–96)
were isolated and characterized by FT-IR, 1H-NMR, and
13
C-NMR, from the roots and fruits of A. carambola with
excellent antioxidant properties. Among them, compounds 83,
84, 94, and 95 are alkyl phenols in structure. Pang et al. (2016)

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Luan et al. Phytochemistry and Pharmacology of Averrhoa carambola

FIGURE 3 | Chemical structures of compounds isolated from A. carambola.

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Luan et al. Phytochemistry and Pharmacology of Averrhoa carambola

FIGURE 3 | (Continued).

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Luan et al.
FIGURE 3 | (Continued).
compared the phenolic and flavonoid compound content of four
popular cultivars of A. carambola that originated from southern
China and found that the contents of bound, free, and total
phenolic for four cultivars were 6.4–19.7, 162.5–286.8, and
174.5–293.1 mg gallic acid equivalents per 100 g fresh weight,
respectively. The contents of bound, free, and total flavonoid of
the four cultivars were 1.1–7.8, 100.7–234.0, and 104.4–235.1 mg
catechin equivalents per 100 g fresh weight, respectively, which
indicated that a certain amount of non-flavonoid phenolic
substances exist. These phenolic compositions are summarized
in Table. Their chemical structures were drawn by ChemBioDraw
Ultra 14.0 and are presented in Figure 3.
Phenylpropanoids
Phenylpropanoids are a kind of plant-derived organic compound,
and these compounds are mainly derived from phenylalanine and
tyrosine (Yao et al., 2020). At present, 18 phenylpropanoids
(97–114) have been successfully separated and chemically
identified by analyses of spectroscopic data including 1H-NMR
and 13C-NMR, from the fruits and roots of A. carambola. These
compounds can be classified as simple phenylpropanoids,
lignans, and coumarins based on their substructure type.
Among them, four simple phenylpropanoids (97–101) have
been reported for the A. carambola fruit, twelve lignans
(102–110) were primarily achieved and identified from A.
carambola roots. Furthermore, four coumarins (111–114) have
Frontiers in Pharmacology | www.frontiersin.org
Phytochemistry and Pharmacology of Averrhoa carambola
been found in A. carambola fruit, compounds reticulol (111) and
6-O-methyl-reticulol (112) are isocoumarins in structure, 5-
methylmellein (113) and 7-hydroxy-5- methylmellein (114)
are dihydroisocoumarins in structure. Reticulol (111)
displayed moderate antioxidant capacity against DPPH with
the IC50 value of 58 μg/ml (Sritharan et al., 2019). These
phenylpropanoid constituents are summarized in Table 1 and
the corresponding chemical structures were also draw by
ChemBioDraw Ultra 14.0 and are presented in Figure 3.
Other Compounds
Up to date, apart from the chemical compounds listed above, few
compounds (115–132) have been investigated and summarized
in Table 1 and the corresponding chemical structures were
presented in Figure 3. Briefly, compounds 117 and 118 are
identified as benzoic acid, compounds 121–125 are quinones,
compounds 126 and 127 are tetrahydroisoquinoline alkaloids,
and components 128–132 are identified as alkyl glycosides.
Among them, 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-
dione (122) was obtained and characterized from A.
carambola roots showing multiple bioactive properties both in
cell and animal experimental studies, including anti-cancer (Gao
et al., 2015; Chen et al., 2017b), anti-diabetic nephropathy (Lu
et al., 2019), anti-obesity (Li et al., 2016), anti-hyperglycemic
(Zhang et al., 2020), anti-inflammatory (Xie et al., 2016), and
neuroprotective activities (Wei et al., 2018).
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Luan et al.
PHARMACOLOGICAL ACTIVITIES
Antioxidant Activity
Among pharmacologically active substances, natural antioxidants
have gained widespread attention because they are safe and have
low toxicity, and promising biological functions (Rufino et al.,
2011). A. carambola leaves (ACL) supposedly exhibit the most
potent antioxidant activities determined by DPPH, FRAP, and
TEAC assays (Table 2). Phytochemical studies have shown that
these leaves are rich in phenolic and flavonoid components,
which are closely associated with antioxidant effects; this
indicates that ACL is potentially an abundant source of
natural antioxidants and could help prevent and treat
oxidative stress-related diseases (Chen et al., 2017a). In a
systematic comparison between twenty locally available fruits
planted in Sri Lanka, Silva and Sirasa (2018) demonstrated that A.
carambola had the third most potent antioxidant properties based
on assays against FRAP and DPPH activities, total flavonoid
content, total phenolic content, and vitamin C content. Siddika
et al. (2020) found that the methanol extract of A. carambola
leaves (MEACL, at 50–375 μg/ml) demonstrated dose-dependent
moderate antioxidant activity when assayed against DPPH and
ABTS+, with IC50 values of 62.0 and 6.0 μg/ml, respectively. Other
phytochemical investigations have shown MEACL is rich in
phenolics, which could be the drive behind its radical
scavenging activity. Using paper spray ionization (PSI)
coupled to high-resolution mass spectrometry, one study
revealed that a bioactive compound, norathyriol, isolated from
ethanol extracts of the bark of A. carambola (EEBAC) had
antioxidant properties. EEBAC (at concentrations of 1.0, 3.0,
10, 30, and 100 μg/ml) displayed concentration-dependent
antioxidant characteristics via suppressing the activities of
α-glucosidase, elastase, ABTS+, DPPH, and tyrosinase enzyme,
with IC50 values of 7.15, 20.34, 26.29, 55.55, and 56.46 μg/ml,
respectively (Islam et al., 2020). Compound (40) at 2.5, 5, and
10 μg/ml, has shown powerful antioxidant effects against DPPH
and ABTS+, with corresponding IC50 values of 4.9 and 9.63 μg/ml
(Islam et al., 2020). The efficiency and potency of crude extracts
or bioactive ingredients from A. carambola suggest it is a
promising antioxidant in the pharmaceutical and functional
food industries.
Anti-Hyperglycemic Activity
Diabetes mellitus is characterized by a chronic hyperglycemic
condition possibly induced by insulin deficiency, damage to
insulin signaling, or non-autoimmune etiology or caused by a
remarkably diminished insulin sensitivity (Teng et al., 2018). This
disorder poses a significant public health care problem, with its
prevalence continuing to rise globally (Chen et al., 2019). Type 2
diabetes mellitus, in particular, is primarily distinguished by
insulin resistance and β cell dysfunction, which cause insulin
secretion reduction (Uuh-Narváez et al., 2021). Diabetes mellitus
patients can die if they develop diabetic kidney disease.
In the past 5 years, several studies have extensively explored
the antidiabetic potential of A. carambola using various
experimental models. The findings have revealed that A.
carambola and its glycosides exhibit outstanding antidiabetic
Frontiers in Pharmacology | www.frontiersin.org
Phytochemistry and Pharmacology of Averrhoa carambola
features, and insights into the underlying mechanisms have
also been provided, although they are not yet fully understood.
The underlying mechanism of the anti-hyperglycemic activity of
crude extracts or bioactive substances from A. carambola is
presented in Table 2 and Figure 4.
Crude Extract
Evaluations of the hypoglycemic activity of A. carambola crude
extracts on rats and mice have been conducted with encouraging
results. In one such assessment, mice with STZ-induced diabetes
given root extracts of A. carambola (REAC at daily doses of 150,
300, 600, and 1,200 mg/kg for 21 days) orally had significantly
decreased blood glucose, TC, TGs, and FFAs levels and elevated
insulin content in their serum. Mechanically, REAC markedly
downregulated pro-apoptosis caspase-3/8/9 and Bax protein
expressions and upregulated anti-apoptotic Bcl-2 protein
expression. Additionally, REAC prevented pancreatic β cell
apoptosis in these mice (Xu et al., 2014). The findings of that
investigation suggest that REAC possesses remarkable
hyperglycemic abilities that could improve metabolic functions
and suppress the apoptosis of pancreatic β cells.
Research into the anti-hyperglycemia activities of REAC on
regulating the TLR4/NF-κB signaling pathway in STZ-induced
diabetic mice showed that REAC (at daily doses of 300, 600, and
1,200 mg/kg, i.g. for 14 days) decreased the serum contents of
fasting blood glucose (FBG), TNF-α, and IL-6 significantly and
downregulated TLR4 and NF-κB protein and mRNA expressions
in pancreatic tissue (Xu et al., 2015). In their assessment of the
protective features of REAC on renal function injury in STZ-
stimulated diabetic mice, Xu et al. (2017) found that REAC
treatment reduced FBG, blood urea nitrogen (BUN), and
creatinine levels in serum significantly, strengthened SOD,
GSH-Px, and CAT activities considerably, and lessened MDA
levels and Cyto-C, AIF, and caspase-3 protein expressions in the
kidney tissues of the mice.
After orally treating fluoride-induced hyperglycemia,
hypercholesterolemia, and oxidative stress in rats with fruit
powder from A. carambola (FPAC, at daily doses of 2.5, 5.0,
and 10 g for 30 days), the plasma glucose level and G-6-pase,
SGOT, SGPT, ACP, and ALP activities reduced notably, while the
activities of hepatic glycogen, hexokinase, and FPAC increased
dose-dependently. Increments in the atherogenic index of plasma
(AIP), total lipids (TL), TC, TG, LDL-C, and VLDL-C in plasma,
TL, TC, and TG in the liver and the decrease in HDL-C were also
reversed. Additionally, FPAC prompted an increase in CAT,
SOD, GSH-Px, GSH, and total ascorbic acid (TAA) activities
significantly, and a decline in MDA content in the hepatic and
renal tissues of rats (Vasant and Narasimhacharya, 2014).
STZ-induced diabetic mice receiving juice extracts from A.
carambola (JEAC) intragastrically (at daily doses of 25, 50, and
100 mg/kg for 21 days) have displayed markedly reduced FBG,
FFA, MDA, TC, TG, serum creatinine (Scr), and BUN levels and
significantly increased insulin, sorbitol dehydrogenase (SDH),
cAMP, and SOD activities. In the same study, diabetes-instigated
changes in kidney tissues, including thickened and tubular
basement membranes and glomerular hypertrophy, greatly
improved, and the expressions of related mRNAs and
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TABLE 2 | Pharmacological effects of crude extracts and bioactive compounds of A. carambola.

Pharmacological Compounds/ Types Testing subjects Doses/Duration Effects/Mechanisms References

activity Extracts

Antioxidant activity
MEACL In vitro DPPH and ABTS+ assays 50–375 μg/ml Showed moderate free radical Siddika et al. (2020)
scavenging activity against
DPPH and ABTS+ free radical
with the IC50 were 62.0 and
6.0 μg/ml, respectively
PRAC In vitro DPPH and ABTS+ assays 0.5–2.5 mg/ml Showed significant free radical Liao et al. (2019b)
scavenging activity against
DPPH and ABTS+ with the IC50
of 0.10 and 0.33 mg/ml,
respectively
EEBAC In vitro α-glucosidase, elastase, ABTS+, 1.0, 3.0, 10, 30, and Showed significant antioxidant Islam et al. (2020)
DPPH, and tyrosinase enzyme 100 μg/ml activity, and the IC50 values
assays were 7.15, 20.34, 26.29, 55.55
and 56.46 μg/ml, respectively
40 In vitro DPPH and ABTS+ assays 2.5, 5, and 10 μg/ml Showed significant radical Islam et al. (2020)
scavenging activity against the
DPPH and ABTS+ with the IC50
values of 4.9 and 9.63 μg/ml,
respectively
Anti-hyperglycemic activity
REAC In vivo STZ-induced diabetic mice 150, 300, 600, and Blood glucose, TC, TGs, and Xu et al. (2014)
1,200 mg/kg, daily for FFAs levels ↓; insulin level ↑;
21 days caspase-3, caspase-8,
caspase-9, and Bax protein
expressions ↓; Bcl-2 protein
expression ↑
REAC In vivo STZ-induced diabetic mice 300, 600, and FBG, IL-6 and TNF-α levels ↓; Xu et al. (2015)
1,200 mg/kg, i.g., daily TLR4 and NF-κB mRNA and
for 14 days protein expression
REAC In vivo STZ-induced diabetic mice 300, 600, and FBG, Cr, BUN, and MDA levels Xu et al. (2017)
1,200 mg/kg, i.g., daily ↓; SOD, GSH-Px, CAT activities
for 42 days ↑; Cyto-C, AIF, and caspase-3
protein expressions ↓
FPAC In vivo Fluoride-induced hyperglycemia, 2.5, 5.0, and 10 g, i.g., Blood glucose, G-6-pase, Vasant and
hypercholesterolemia, and for 30 days SGOT, SGPT, ACP, and ALP Narasimhacharya
oxidative stress of rat’s model levels ↓; hepatic glycogen and (2014)
hexokinase, and FRAP
activities ↑; plasma AIP, TL, TC,
TG, LDL-C, VLDL-C, hepatic
lipids-TL, TC and TG levels ↓;
HDL-C level ↑; CAT, SOD, GPx,
GSH, TAA activities ↑; MDA
level ↓
JEAC In vivo STZ-induced diabetic mice 25, 50, and 100 mg/kg, FBG, FFA, TC, TG, Scr, BUN, Pham et al. (2017)
i.g., once a day for and MDA levels ↓; SDH, cAMP,
21 days SOD, and insulin activities ↑;
CTGF and TGF-β1 mRNA and
protein expressions ↓
JEAC In vivo STZ-induced diabetic mice 5, 10, and 20 g/kg, FBG, blood glucose, area Yang et al. (2019a)
orally, once a day for under curve, LDH, GC and
14 days pyruvate ↓; FINS level ↑
TFACL In vivo Alloxan-induced diabetic mice 0.2, 0.4, and 0.8 g/kg, FBG level ↓; glucose Liu et al. (2013)
and STZ-induced diabetic rats i.g., daily for 7 days tolerance ↑
EEACB In vivo STZ-induced diabetic mice 50 and 100 mg/kg, i.g., Blood glucose level ↓ Islam et al. (2020)
for three successive
days
47 In vivo STZ-induced diabetic rats 20 and 50 mg/kg, i.g., Serum blood glucose level ↓; Cazarolli et al. (2012)
48 for 3 h insulin secretion ↑
48 In vitro 14
C-glucose uptake in rat soleus 50 and 100 μM for 1 h Glucose uptake and glucose Cazarolli et al. (2009)
muscle transport ↑
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TABLE 2 | (Continued) Pharmacological effects of crude extracts and bioactive compounds of A. carambola.

Pharmacological Compounds/ Types Testing subjects Doses/Duration Effects/Mechanisms References

activity Extracts

105 In vivo STZ-induced diabetic mice 20, 40, and 80 mg/kg, FBG, FINS, and ISI levels ↓; NF- Wen et al. (2013)
106 i.g., daily for 14 days κB, caspase-3, caspase-8,
caspase-9, and Bax protein
expressions ↓
121 In vivo STZ-induced diabetic mice 30, 60, and 120 mg/kg, FBG, TC, TG, FFA, GHb, FINS, Qin et al. (2019)
i.g., once daily, for MCP-1, TNF-α, IL-6 and MDA
21 days levels ↓; SOD, GSH activities ↑
121 In vivo STZ-induced diabetic mice 30, 60, and 120 mg/kg, TLR4, MyD88, p-NF-κB, TNF- Qin et al. (2020)
i.g., once daily, for α, and IL-6 mRNA and protein
21 days expression levels ↓
122 In vivo Type 2 diabetic KKAy mice 12.5, 25, and 50 mg/kg, FBG, AGEs glycosylated Zheng et al. (2013)
i.g., daily, for 56 days protein and TC levels ↓; albumin
level ↑
122 In vivo Type 2 diabetic KKAy mice 12.5, 25, and 50 mg/kg, FBG level ↓; RAGE, NF-B, TGF- Zheng et al. (2021)
i.g., daily, for 56 days β1 and CML protein expression
levels ↓
122 In vivo DN model established by STZ in 12.5, 25, and 50 mg/kg, TC, TG, HDL, LDL, Scr, BUN, Lu et al. (2019)
TLR4 knockout mice and wild- i.g., daily for 28 days and blood glucose ↓; IL-6 and
type mice TNF-α level ↓; TLR4, MyD88
and NF-κB mRNA and protein
expressions ↓
122 In vitro HG-induced HK-2 cells 30 μM for 48 h Blood glucose ↓; Vimentin Zhang et al. (2019)
mRNA and protein level ↑;
TLR4 and E-cadherin mRNA
and protein levels ↓; BAMBI ↑;
Smad2/3 ↓
122 In vivo Diabetic kidney disease mice 12.5, 25, and 50 mg/kg, TC, TG, LDL-C, FBG, CysC, Zhang et al. (2020)
model induced by Wild type and i.g., once daily, for and urinary albumin levels ↓;
TLR4 knockout 28 days TLR4, TGF-β1 and Smad2/3
mRNA and protein levels ↓
Antihyperlipidemic activity
IFRF In vivo Murine model Diets formulations, i.g., TG, TC, HDL, and LDL levels ↓ Herman-Lara et al.
FF for 30 days (2014)
MEACL In vivo Poloxamer-407-induced NM TC, TG, LDL-C, VLDL-C and AI Saghir et al. (2016)
hyperlipidemic rat model levels ↓
MEACL In vivo HFD-induced hyperlipidemic rats 250, 500, and TC, TG, LDL-C, VLDL-C, and Aladaileh et al. (2019)
1,000 mg/kg, i.g., daily, AI ↓; HDL-C ↑; GSH, GPx,
for 35 days SOD, CAT activities ↑; MDA
level ↓
Anti-obesity activity
CEPAC In vitro 3T3-L1 preadipocytes 10, 100, 500, and TG accumulation ↓; PPAR-γ Rashid et al. (2016)
1,000 mg/ml and C/EBPα mRNA
expressions ↓; PPAR-α mRNA
expression ↑
122 In vivo high-fat diet (HFD) in mice 12.5, 25, and 50 mg/kg, BW and adipose tissue Li et al. (2016)
i.g., daily for 28 days weights, blood glucose, insulin,
TC, TG, FFA, IL-6, TNF-α levels
↓; TLR4 and MyD88
expressions ↓; insulin
secretion ↑
Antitumor activity
ACE In vivo DENA-induced and CCl4- 25 mg/kg, i.g., for five Tumor incidence, tumor yield, Singh et al. (2014)
promoted liver cancer in mice consecutive days tumor burden ↓; LPO level ↓;
GSH, SOD, CAT, total proteins
content activities ↑
MEACL In vivo EAC cell bearing mice 25 and 50 mg/kg, i.g., viable cells and body weight ↓; Siddika et al. (2020)
for 5 days survival time ↑; Hgb, WBC,
RBC numbers ↑; p53 and Bax
protein expression ↑
122 In vitro Human breast cancer MCF-7 and 10, 32, 100 μM for 24 h Caspase-3/7, -8, and -9 Gao et al. (2015)
BT20 cells activities ↑; TRAIL-R1, TRAIL-
R2, Bad, and BID protein
expressions ↑; cIAP, XIAP, and
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TABLE 2 | (Continued) Pharmacological effects of crude extracts and bioactive compounds of A. carambola.

Pharmacological Compounds/ Types Testing subjects Doses/Duration Effects/Mechanisms References

activity Extracts

Survivin protein expressions ↓;

G1 phase cell cycle arrest, ROS
↑; NF-κB ↓
122 In vivo Transplanted 4T1 breast cancer 25, 50 and 100 mg/kg, Survival time ↑; tumor growth ↓; Chen et al. (2017b)
cells bearing mouse i.g., for 14 days TNF-α, IL-6, IL-12, TGF-β,
VEGF ↓; Bax, cleaved
caspases-3 and -9 ↑; Bcl-2,
MMP-2 and -9, NF-κB and
IκBα ↓
122 In vitro Radio-sensitivity of 4T1 breast 100 μM for 2 or 24 h TIE, TRD ↓; radio-sensitivity of Muhammed et al.
carcinoma cell lines the 4T1 cells ↑ (2019)
122 In vitro Lung cancer H1299 cells 4.0, 6.0, and 8.0 μg/ml Cell apoptosis ↑; ERK/MAPK ↓; Zhou et al. (2019)
for 24 h inhibition rates were 22.50,
30.13, and 58.87%,
respectively
122 In vivo Hepatocarcinoma in nude mice 25, 50, and 100 mg/kg, Tumor weight ↓; liver and Wu et al. (2020a)
i.g., daily for 12 days spleen indexes ↓; IL-2 and IL-
10 levels ↓; inhibition rates were
66.39, 63.11, and 47.33%,
respectively; WBC, HGB, and
PLT numbers ↑; TLR4, MyD88,
and NF-κB expressions ↓
Anti-inflammatory activity
EEACL In vivo Croton oil-induced mouse ear 0.03–1.0 mg/ear Edema (IC50: 0.05) ↓; MPO Cabrini et al. (2011)
edema activity (IC50: 0.22) ↓
PFSCW In vivo Adult female Swiss mice 100 and 300 mg/kg Paw edema ↓ Leivas et al. (2016a)
122 In vivo Pancreatic β-cell line Min6 cells 10, 15, and 20 μmol/L TNF-α, IL-6 and MCP-1 level ↓; Xie et al. (2016)
cleaved-caspase-3, -8 and -9,
TLR4, MyD88, and NF-KB
expressions ↓; Bcl-2/Bax
ratio ↑
Hepatoprotective activity
FPEAC In vivo Leptin receptor- deficient (db/db) 10, 20, and 30 g/kg, i.g., TG, TC, LDL-C, and NEFA level Pang et al. (2017)
mice daily, for 8 weeks ↓; AST and ALT activities ↓;
HDL-C level ↑; p-AMPK protein
expression ↑; SREBP-1c, FAS
and SCD1 mRNA and protein
expression levels ↓; mircoRNA-
34a and mircoRNA-33
expression levels ↓
FJAC In vivo STZ-induced diabetic mice 5, 10, and 20 g/kg, i.g., MAD and cAMP levels ↓; SDH, Yang et al. (2018)
daily for 14 days MDA, and SOD activities ↑
EACR In vivo CCl4-induced acute liver injury in 0.3, 0.6, and 1.2 g/kg, f AST, ALT, IL-1, IL-6, MDA Huang et al. (2019)
mice i.g., dialy, for 7 days levels ↓; SOD, GSH, GSH-Px
activities ↑; TNF-α, NF-κB,
caspase-3 protein expression
levels ↑
EACR In vivo Liver fibrosis (HF) rats induced by 0.25, 0.5, and 1.0 g/kg, Albumin/globulin (A/G) ratio ↑; Liang et al. (2020b)
CCl4 i.g., dialy, for 28 days TBIL and TC levels ↓; NF-κB
and Bax expression levels ↓;
Bcl-2 expression level ↑
EACR In vivo CCl4-induced acute liver injury in 0.25, 0.5, and 1.0 g/kg, AST, ALT, AKP, Hyp, HA, LN, Huang et al. (2020)
rats i.g., dialy, for 8 weeks Col III, Col IV, MDA levels ↓;
SOD and GSH-Px activities ↑;
COL-1a1, α-SMA, TIMP2,
TGF-β1, Smad-2 and Smad-4
mRNA expression levels ↓;
α-SMA, TIMP2, TGF-β1,
Smad-2, Smad-3 and Smad-4,
Bax and cleaved caspase-3
proteins expression levels ↓;
Smad-7 mRNA expression and
(Continued on following page)

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Luan et al. Phytochemistry and Pharmacology of Averrhoa carambola

TABLE 2 | (Continued) Pharmacological effects of crude extracts and bioactive compounds of A. carambola.

Pharmacological Compounds/ Types Testing subjects Doses/Duration Effects/Mechanisms References

activity Extracts

Smad-7 and Bcl-2 protein

expression ↑
Cardioprotective activity
AEAC In vivo Rats with ventricular remodelling 50, 100, and TGF-β, Ang II, iNOS, ECE, ET-1 Liang et al. (2020a)
induced by isoprenaline 200 mg/kg, i.g., daily, for levels and expressions ↓; VR
14 days index, CVF ↓; tNOS, eNOS
protein expression levels ↑
Antihypertensive activity
AELAC In vivo Normotensive rats 12.5–50.0 mg/kg, i.v. MAP ↓; Ca2+-free medium ↓ Soncini et al. (2011)
EEACR In vivo Normal rats 150, 300, and Blood pressure ↓ Tang et al. (2017)
600 mg/kg, i.g.
FACF In vivo Normal rats and rats with 300, 600, and SBP, DBP, MBP, blood Huang et al. (2017)
hypertension induced by L-NAME 1,200 mg/kg, i.g., daily, pressure ↓
for 5 weeks
Neuroprotective activity
122 In vivo APP/PS1 transgenic AD mice 12.5, 25, and 50 mg/kg, Spatial learning and memory Wei et al. (2018)
i.g., once a day for deficit, fear memory deficit
21 days apoptosis and loss of neuron ↑;
Bcl-2/Bax ratio ↑
122 In vitro PC-12 cells 5, 10, and 20 μmol/L Bcl-2 mRNA and protein Wei et al. (2018)
expressions ↑; Bax mRNA and
protein expressions ↓;
caspase-3 and caspase-9
expressions ↑; Bcl-2/Bax
ratio ↑
122 In vitro SH-SY5Y cells induced by 5, 10, and 20 μmol/L cell viability loss and apoptosis Lu et al. (2020)
Aβ1-42 ↓; Bax, caspase-3, caspase-8
and caspase-9 protein
expression levels ↓; Bcl-2
protein expression ↑
Reducing UVB-induced skin damage
EFAC In vitro Human HaCaT keratinocytes 50, 100, and 250 µg/ml Apoptotic cells number ↓; Ronpirin et al. (2016)
AFAC induced by UVB caspase 3 expression ↓; CPD ↓

NM, not mentioned; ACL, A. carambola leaves; MEACL, methanol extract of A. carambola leaves; EEBAC, ethanol extracts of bark from A. carambola; REAC, root extracts of A.
carambola; FPAC, fruit powder of A. carambola; JEAC, juice extracts of A. carambola; TFACL, total flavones from A. carambola leaf; EEACB, ethanol extracts of A. carambola bark;
MEACL, methanolic extract of A. carambola leaves; CEPAC, crude extract from peel of A. carambola; PEFAC, a homogenous polysaccharide extracted from the fruit of A. carambola; ACE,
A. carambola extracts; EEACL, ethanol extract of A. carambola leaves; FPEAC, free phenolic extract from A. carambola; FJAC, fruit juice of A. carambola; EACR, extract of A. carambola
root; AEAC, aqueous extract of A. carambola; AELAC, aqueous extract of leaves of A. carambola; EEACR, ethanol extracts of A. carambola root; FACF, flavonoids in A. carambola fruit;
EFAC, ethanol fractions of A. carambola; AFAC, aqueous fractions of A. carambola; 40, Norathyriol; 47, Carambolaflavone A; 48, Carambolaflavone B; 105, (+)-lyoniresinol 3α-O-β-D-
glucopyranoside; 106, (−)-lyoniresinol 3α-O-β-D-glucopyranoside; 121, 2-methoxy-6-nonyl-cyclohexa-2,5-diene-1,4-dione; 122, 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione.

proteins, such as CTGF and TGF-β1, in kidney tissues markedly
decreased after JEAC treatment (Pham et al., 2017). JEAC (at
daily doses of 5, 10, and 20 g/kg, i.g. for 14 days) has also been
proven to considerably decrease FBG levels, blood glucose, area
under the curve, LDH, glucagon (GC), and pyruvate in serum and
increase fasting insulin (FINS) levels in STZ-induced diabetic
mice, indicating that this extract could lessen hyperglycemia and
hyperlipidemia, suppressing DN progression and development; it
is a potential candidate agent for treating or preventing DN (Yang
et al., 2019a).
Liu et al. (2013) reported that the total flavones from A.
carambola leaf (TFACL at daily doses of 0.2, 0.4, and 0.8 g/kg,
i.g. for 7 days) significantly lowered FBG levels and enhanced
glucose tolerance in mice and rats with diabetes mellitus. The
STZ-induced diabetic mice also received ethanol extracts of A.
carambola bark (EEACB) orally (at daily doses of 50 and
100 mg/kg for three successive days), which drastically
decreased their level of blood glucose 150 min after orally
receiving a single dose of glucose solution (1.0 g/kg);
100 mg/kg EEACB triggered a higher blood glucose level
decline than 50 mg/kg EEACB (Islam et al., 2020). These
results suggest that A. carambola is a potential hypoglycemic
drug for the prevention and treatment of diabetes.
6.2.2 Isolated Compounds
As previously mentioned, some compounds, including 47, 48,
100, 101, 120, and 121, isolated and identified from A. carambola
have been tested for their potential anti-hyperglycemic activity in
vivo. Normal hyperglycemic rats receiving an oral treatment of
flavonoid carambolaflavone A (at doses of 20 and 50 mg/kg) (47)
and carambolaflavone B (at doses of 20 and 50 mg/kg) (48)
extracted from A. carambola leaves demonstrated decreased
glycemia levels, suggesting a potential hypoglycemic effect.
Glycogen levels in the muscle and liver also increased sharply
(Cazarolli et al., 2012). Another study by the same authors also
found 50 mg/kg of carambolaflavone B (48) to notably decrease
blood glucose levels in diabetic rats and provoke glucose-
triggered insulin secretion after oral treatment of the

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Luan et al.
FIGURE 4 | Schematic representation of the underlying mechanism of anti-hyperglycemic activity of crude extracts or isolated compounds from A. carambola.
hyperglycemic rats. Additionally, a noteworthy stimulatory
function of compound 48 (at concentrations of 50 and
100 μM) on 14C-glucose uptake was observed, but treatment
with inhibitors, including wortmannin, RO318220, and
PD98059, reversed this activity. Interestingly, 100 μM of
compound 48 and 10 nM of insulin had no synergistic effect
on glucose uptake (Cazarolli et al., 2009).
Chiral lignan glucosides, (±)-lyoniresinol 3α-O-β-D-
glucopyranoside (LGP1 (105) and LGP2 (106)), isolated from
A. carambola root have been evaluated for health-promoting
properties in LGP1 and LGP2-mediated hypoglycemia against
renal injury in STZ-created diabetic mice. Diabetic mice that
received LGP1 and LGP2 (at daily doses of 20, 40, and 80 mg/kg
for 14 days) yielded contrasting outcomes. While LGP1 markedly
alleviated the histopathological changes in the kidney and
lowered FBG, FINS, and insulin sensitivity index (ISI) levels
and caspase-3/8/9, Bax, and NF-κB protein expressions, LGP2
had no impact (Wen et al., 2013), suggesting that LGP1 could
attenuate and treat the progression of DN through regulating
several molecular targets.
Benzoquinone (121) isolated from the roots of A. carambola
has also been analyzed, and, at doses of 30, 60, and 120 mg/kg, i.g.
once a day for 21 days. It effectively decreased serum FBG, TC,
TG, FFA, MCP-1, TNF-α, GHb, FINS, MDA, and IL-6 levels and
increased SOD and GSH activities in STZ-induced diabetic rats.
Mechanistically, the extract strikingly downregulated TNF-α, IL-
6, MyD88, p-NF-κB, and TLR4 expressions in pancreatic tissues
(Qin et al., 2019; Qin et al., 2020). These findings suggest that
benzoquinone (121) exerts a protective effect against STZ-
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Phytochemistry and Pharmacology of Averrhoa carambola
induced hyperglycemia, and the underlying molecular
mechanism of its impact could be associated with the
suppression of the activation of the TLR4/NF-κB signaling
pathway.
Zheng et al. (2013), Zheng et al. (2021) reported that DMDD
(122) isolated from A. carambola dry roots (at daily doses of 12.5,
25, and 50 mg/kg, i.g. for 56 days) to significantly reduce FBG,
creatinine clearance, proteinuria, Scr, and serum urea-N contents
and glomerular mesangial matrix expansion. It also markedly
improved renal AGE formation, decreased AGE receptor, NF-κB,
TGF-β1, and Nε-(carboxymethyl)lysine expressions in diabetic
mice, and effectively alleviated DN in type 2 diabetic KKAy mice.
However, the underlying mechanism of how DMDD alleviates
DN has yet to be demonstrated; therefore, the precise action
mechanism of DMDD against DN must be explored further (Lu
et al., 2019). STZ-established DN in TLR4 knockout (TLR4−/−,
KO) and wild-type (WT) mice treated orally with DMDD (at
doses of 12.5, 25, and 50 mg/kg for 28 days) lowered serum TC,
TG, HDL-C, and LDL-C, blood glucose content and kidney
function markers, including Scr and BUN, significantly and
increased the quantity and density of podocytes spectacularly,
contributing to DN symptom alleviation. The treatment also
markedly inhibited IL-6 and TNF-α levels and blocked the
TLR4/MyD88/NF-κB signaling pathways. These effects,
though, were notably different in TLR4−/− mice. In vitro,
30 μM DMDD radically subdued TLR4, Smad2, and Smad3
expressions in high glucose (HG)-stimulated HK-2 cells and
diminished BMP and activin membrane-bound inhibitor
(BAMBI) expressions (Zhang et al., 2019). Additionally, the
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Luan et al.
FIGURE 5 | Schematic representation of the underlying mechanism of anti-tumor activity of crude extracts or isolated compounds from A. carambola.
increase in Smad2/3 expression and decrease in BAMBI
expression in HG cultured cells were markedly annulled in
cells treated with TAK-242 (a TLR4 signaling inhibitor). More
importantly, BAMBI gene silencing extraordinarily enhanced the
epithelial-mesenchymal transition (EMT) process and its over-
expression did the opposite in HK-2 cells under HG conditions.
EMT was eased with the pre-administration of DMDD to HK-2
cells, pointing to DMDD’s protective effects on HG-induced
EMT in HK-2 cells via suppressing the TLR4/BAMBI/Smad2/
3 signaling pathways (Zhang et al., 2019). These findings
insinuate that DMDD isolated from A. carambola is a
potential therapeutic drug for DN treatment.
In Zhang et al. (2020) study of the antidiabetic activity of
DMDD isolated from A. carambola roots in Wild type and TLR4
knockout mice with diabetic kidney disease, DMDD (at daily
doses of 12.5, 25, and 50 mg/kg, i.g. for 28 days) caused notable
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Phytochemistry and Pharmacology of Averrhoa carambola
reductions in urinary albumin, TC, TG, LDL-C, FBG, and CysC
levels. The extract also alleviated pathological changes and renal
fibrosis clearly but silencing the TLR4 gene improved the
pathology. Mechanistically, TLR4, TGF-β1, Smad2, and
Smad3 protein expressions in renal tissues decreased
pointedly after DMDD treatment. TGF-β1 and Smad2/3
genes and protein expressions also unusually declined in
TLR4−/− mice than Wild type mice. Furthermore, according
to IHC results, there were strong in situ expressions of TLR4,
TGF-β1, Smad2, and Smad3 in kidney tissues, which were
distinctly weakened after DMDD-treatment. Nevertheless,
TGF-β1, Smad2, and Smad3 levels did not increase in the
TLR4−/− mice with significance when compared with healthy
mice (Zhang et al., 2020). These findings strongly suggest that
TLR4 is critical for DMDD’s protective activity against renal
insufficiency in diabetic mice, and hypoglycemic and anti-
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Luan et al.
fibrosis properties could be regulated by the TLR4/TGF
signaling pathway.
In summary, A. carambola could attenuate oxidative injury
and inflammatory response in rat models by enhancing
antioxidant enzyme activities and decreasing inflammatory
cytokine levels, which result in insulin secretion, as well as
blood glucose and blood lipid metabolism regulation. Some
original findings on active compounds and their related
mechanisms also exist; however, these investigations lack clear
indications of whether these activities stem from a single
substance or synergistic effects of several substances of A.
carambola; therefore, before they can be advanced as bases for
clinical research and exploration of the medicinal values of A.
carambola, further evaluations must be performed.
Anti-Hyperlipidemic Activity
Cardiovascular diseases (CVDs) are among the most common
causes of death globally, with hyperlipidemia representing one of
its main risk factors (Mahdavi et al., 2020; Jayachandran and Qu,
2021). In Herman-Lara et al. (2014) evaluation of the protective
activity of micronized insoluble fiber from the bagasse of A.
carambola as an ingredient of a functional food (FF) or as
micronized insoluble fiber-rich fraction (IFRF) and its effects
in vivo on lipid metabolism in a murine model, serum TG, TC,
HDL-C, and LDL-C decreased after a murine model was treated
with IFRF and FF, with corresponding inhibition rates of 14.2,
25.4, 55.06, and 12.18% by IFRF, and 30.18, 39.47, 35.11, and
43.18% by FF. IFRF treatment also produced higher
hypolipidemic activity and greatly avoided the occurrence of
non-alcoholic fatty liver. Overall, IFRF and FF exerted
hypolipidemic qualities, indicating that the star fruit’s
insoluble fiber is potentially a component of FFs in the
treatment and prevention of CVDs (Herman-Lara et al., 2014).
In Saghir et al. (2016) investigation of the anti-hyperlipidemic
activity of methanolic and aqueous extracts from various A.
carambola parts (such as leaves, stems, and ripe and unripe
fruits), they found that the methanolic extract of A. carambola
leaves (MEACL) had the most potent hypolipidemic effect in
poloxamer-407-induced hyperlipidemic rats and effectively
decreased serum TC, TG, LDL-C, VLDL-C, and atherogenic
index (AI) levels. MEACL (at daily doses of 250, 500, and
1,000 mg/kg, i.g. for 35 days) significantly reduced serum and
liver lipids levels, including TC, TG, LDL-C, VLDL-C, and AI,
elevated HDL-C, and dose-dependently alleviated
histopathological changes in the liver of HFD-induced
hyperlipidemic rats. MEACL also considerably enhanced GSH,
GSH-Px, SOD, and CAT activities and lowered MDA levels.
Furthermore, MEACL treatment inhibited HMG-CoA reductase
and lipase (Aladaileh et al., 2019). These results demonstrate that
MEACL has a hypolipidemic activity it could exert by
ameliorating lipid peroxidation and improving antioxidant
defenses in HFD-fed rats (Table 2).
Anti-Obesity Activity
Obesity-related diseases are increasingly becoming common
public health and social issues. They can cause a multitude of
metabolic disorders closely associated with increased risk of many
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Phytochemistry and Pharmacology of Averrhoa carambola
chronic diseases (Zhu et al., 2015; Li et al., 2016). One study found
that some phytochemicals suppressed adipogenesis and obesity.
According to Rashid et al. (2016), the crude extract from the peel
of A. carambola (CEPAC) (at concentrations of 10, 100, 500, and
1,000 mg/ml) dose-dependently inhibited TG accumulation in
their research. Additionally, 1,000 mg/ml of CEPAC substantially
blocked most of the adipocyte differentiation in 3T3-L1
preadipocytes with no toxicity. The extract also notably
reduced the mRNA expressions of two master adipogenic
transcription factors, PPAR-γ and C/EBPα, and increased the
PPAR-α receptor at the molecular level. In further phytochemical
analyses, the authors recognized (-)-epicatechin as a natural
bioactive molecule responsible for the features presented above
(Rashid et al., 2016). These findings indicate that CEPAC is
potentially promising in treating obesity and obesity-related
disorders.
Per Li et al. (2016) inquiry into the benefits of DMDD against
high-fat diet (HFD)-evoked obesity and insulin resistance in
mice, DMDD (at daily doses of 12.5, 25, and 50 mg/kg, i.g. for
28 days) markedly decreased body and adipose tissue weights and
reduced insulin, blood glucose, TC, TG, FFA, IL-6, and TNF-α
levels in serum. DMDD also significantly downregulated TLR4
and MyD88 protein levels in epididymal adipose tissues,
considerably enhanced insulin secretion, lowered the areas
under the curve, notably heightened SOD and GSH-Px
activities, and decreased MDA content in mice liver tissues (Li
et al., 2016). Based on these results, DMDD possesses potential
benefits that could be used to treat HFD-induced obesity and
insulin resistance, potentially improving the lipid metabolism
process and the suppression of TLR4 protein expression in
adipose tissues (Table 2).
Antitumor Activity
Several studies have demonstrated the significant inhibitory
activity of A. carambola against a variety of tumor cells in vivo
and in vitro and the possible mechanism of the antitumor activity
of crude extracts or isolated compounds from A. carambola
(Table 2 and Figure 5). DENA-induced and CCl4-promoted
liver cancer mice given A. carambola extracts (ACE, at a dose of
25 mg/kg for 5 days) orally resulted in ACE considerably
lowering tumor incidence, tumor yield, and tumor burden.
The treatment also significantly reduced lipid peroxidation
(LPO) levels and elevated GSH, SOD, CAT activities (Singh
et al., 2014). These findings hinted at ACE’s ability to exert a
protective effect against liver cancer in mice and could be used as
a good natural chemo-preventive product against cancer to
further screen active components. Supposedly, MEACL (25
and 50 mg/kg, i.g. once a day for 5 days) significantly reduces
body weight and cell viability, prolongs survival time, and
improves altered hematological parameters (HGB, WBC, RBC)
in Ehrlich ascites carcinoma (EAC) cell-bearing mice. MELA
could induce cancer cell apoptosis through upregulating p53 and
Bax protein expressions at the molecular level (Siddika et al.,
2020).
Gao et al. (2015) also showed that DMDD significantly
suppressed breast cancer MCF-7 and BT20 cell growth, with
the IC50 values ranging from 3.13 to 5.57 μM; DMDD exerted
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Luan et al.
anticancer traits by inducing apoptosis and blocking the cell cycle
at the G1 phase, increasing the generation of intracellular ROS,
which activated the extrinsic receptor and intrinsic mitochondrial
pathways and inhibited NF-κB activation. One study using 4T1
breast cancer cell-bearing mice for in vivo research revealed that
DMDD radically inhibited primary breast tumor growth and
suppressed breast tumor metastasis in the lung and liver, as well
as decreased inflammatory cytokine production, induced cell
apoptosis, and prevented the activation of the TNF-α/NF-κB/
MMPs pathways, prolonging the survival time of tumor-bearing
mice (Chen et al., 2017b). These outcomes imply that DMDD has
potent antitumor features that could help treat metastatic breast
cancer.
Muhammed et al. (2019) explored the radio-sensitivity of 4T1
tumor cells treated with DMDD extracted from A. carambola
roots, by analyzing the TIE and TRD of the in vivo 2 and 24 h
treatment groups compared with the untreated control group.
The threshold ionization energy (TIE) and threshold radiation
dose (TRD) was determined utilizing a novel method that
employs a laser trapping technique for single and multiple cell
ionizations. Per the findings, treatment periods increased, and
TIE and TRD notably decreased, pointing to DMDD’s powerful
enhancement effect on 4T1 cell radio-sensitivity. However, TRD
diminished with mass regardless of the intervention. TRD
analyses of single vs multiple cells ionizations within each
group continuously demonstrated the same behavior even
after treatment. The underlying elements for these observed
relations could be explained in terms of radiation,
hyperthermia, and chemo effects (Muhammed et al., 2019).
DMDD treatment (at 4.0, 6.0, and 8.0 μg/ml for 24 h) has
been shown to dramatically and dose-dependently inhibit the
proliferation, migration, and invasion of H1299 cells, with
inhibition rates of 22.50, 30.13, and 58.87%, respectively. The
same research determined that DMDD also induced the
apoptosis of H1299 cells, with the mechanism possibly
associated with the suppression of the ERK/MAPK pathway
(Zhou et al., 2019).
Wu et al. (2020a) assessed the antitumor effect of DMDD on
hepatocarcinoma in nude mice and its mechanism, the tumor
weight in mice decreased significantly, with tumor inhibition
rates for the three doses amounting to 66.39, 63.11, and 47.33%,
respectively, after daily oral treatment with DMDD at 25, 50, and
100 mg/kg for 12 days. The tumor and organ indexes, including
liver and spleen, and IL-2 and IL-10 serum levels also notably
decreased, and the amounts of WBC, HGB, and PLT dramatically
increased. Additionally, the expression of TLR4, MyD88, and NF-
κB reduced markedly. These results suggest that DMDD has
promising anticancer properties, with its mechanism of action is
possibly linked to the repression of the TLR4/MyD88/NF-κB
signaling pathways (Table 2).
Anti-Inflammatory Activity
The evaluation of the anti-inflammatory effects of the ethanol
extract of A. carambola leaves (EEACL), its ethyl acetate, butanol,
and hexane fractions, and two flavonoids against skin
inflammation in mice with croton oil-stimulated ear edema
revealed that topically used EEACL (at concentrations of
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Phytochemistry and Pharmacology of Averrhoa carambola
0.03–1.0 mg/ear) shrunk the edema dose-dependently, with an
ID50 value of 0.05 at concentrations of 0.02–0.13 mg/ear and
maximum inhibition of 73% at a concentration of 0.6 mg/ear.
EEACL also suppressed myeloperoxidase (MPO) activity, with an
ID50 value of 0.22 and a maximum inhibition of 61% at a
concentration of 0.6 mg/ear. Furthermore, all the fractions
examined markedly curbed edema formation and lowered
MPO activity. Additional evaluations found that the ethyl
acetate fraction of EEACL was the most effective inhibitor of
MPO activity and edema formation, with inhibition rates of 54
and 75%, respectively (Cabrini et al., 2011). Unfortunately,
EEACL bioactive substances against skin inflammation have
not been tested extensively so far; therefore, they require
further scrutiny to be optimized and developed into effective
remedies for preventing and treating skin disorders.
GC-MS analyses of a homogenous polysaccharide extracted
from the fruit of A. carambola (PFSCW, Mw 40 kDa) established
that it consisted mainly of arabinose, galactose, and galacturonic
acid in a molar ratio of 12.3:1.7:86.0. Methylation and NMR
spectroscopy examination identified a substituted galacturonan
composed of (1→4)-linked-α-D-Galp A units with a branch at O-
2 by (1→5)-linked-α-L-Araf and terminal-α-L-Araf and α-D-
Galp A units as components of PFSCW. PFSCW treatment (at
doses of 100 and 300 mg/kg) drastically reduced intraplantar
formalin-injected paw edema, with an inhibition rate of 53% at a
dose of 300 mg/kg, suggesting that the extract has moderate anti-
inflammatory properties (Leivas et al., 2016a). Xie et al. (2016)
demonstrated that DMDD (at concentrations of 10, 15, and
20 μM) significantly inhibited palmitic acid (PA)-stimulated
inflammation in pancreatic Min6 cells by strongly obstructing
the TLR4/MyD88/NF-KB pathways, which lowered the
generation of inflammatory cytokines (TNF-α, IL-6, and MCP-
1), downregulating cleaved-caspase-3/8/9 protein expression,
elevating the Bcl-2/Bax ratio, and decreasing TLR4, MyD88,
and NF-KB protein expressions. These outcomes hint at
DMDD’s ability to reverse PA-stimulated Min6 cell
dysfunction via alleviating cell apoptosis and inflammatory
response, with the underlying mechanism of action almost
certainly associated with the suppression of the TLR4/MyD88/
NF-κB signaling pathways (Table 2).
Hepatoprotective Activity
An evaluation of the hepatic steatosis alleviating activity of a free
phenolic extract of A. carambola (FPEAC) in leptin receptor-
deficient (db/db) mice to clarify the underlying mechanisms of
action for modulating hepatic lipogenesis found that FPEAC (at
daily doses of 10, 20, and 30 g/kg, i.g. for 8 weeks) considerably
lowered LDL-C, TG, TC, non-esterified fatty acid (NEFA) levels,
and AST and ALT activities, elevated serum HDL-C level, and
reduced TG content in the liver. Mechanically, FPEAC drastically
downregulated sterol regulatory element-binding protein-1c
(SREBP-1c), fatty acid synthase (FAS), and stearoyl-CoA
desaturase 1 (SCD1) expressions in hepatic tissues and
markedly upregulated p-AMPK α levels. More importantly,
FPEAC significantly downregulated microRNA-34a and
microRNA-33 expressions, which regulate the AMPK/SREBP-
1c/FAS signaling pathway (Pang et al., 2017). These findings
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Luan et al.
indicate that FPEAC has a compelling hepatic steatosis mitigating
effect, partially through suppressing the signal transmission of
hepatic lipogenesis. According to Yang et al. (2018), the fruit juice
of A. carambola (FJAC, at daily doses of 5, 10, and 20 g/kg, i.g. for
14 days) showed potential hepatoprotective properties; it reduced
MAD and cAMP levels and increased SDH, MDA, and SOD
activities in the liver of mice with STZ-induced diabetes.
In one study, mice with acute liver injury given the extract of
A. carambola roots (EACR, at daily doses of 0.3, 0.6, and 1.2 g/kg
for 7 days) had significantly lower serum CCl4, AST, ALT, IL-1,
and IL-6 levels and liver MDA levels but considerably increased
SOD, GSH, and GSH-Px activities. At the molecular level, TNF-α,
NF-κB, and caspase-3 protein expressions were significantly
downregulated in the liver. HE staining showed that the liver
injury was eased (Huang et al., 2019). In another investigation,
EACR (at daily doses of 0.25, 0.5, and 1.0 g/kg, i.g. for 28 days)
substantially increased the albumin/globulin (A/G) ratio, reduced
total bilirubin (TBIL) and TC levels in the liver microstructure of
rats with CCl4-induced liver fibrosis (HF), markedly lessened NF-
κB and Bax protein expressions, and considerably augmented
Bcl-2 protein expression (Liang et al., 2020b). Rats with CCl4-
instigated chronic liver injury treated intragastrically with EACR
(at doses of 0.25, 0.5, and 1.0 g/kg for 56 days) displayed
drastically decreased serum AST, ALT, AKP, and Hyp content,
serum hepatic fibrosis biomarkers (HA, LN, Col III, and Col IV),
and liver tissue MDA content and increased SOD and GSH-Px
capacities. EACR also considerably reversed the elevation in
COL-1a1, α-SMA, TIMP2, TGF-β1, and Smad-2 and -4
mRNA expressions and inhibited α-SMA, TIMP2, TGF-β1,
Smad-2, -3, -4, Bax, and caspase-3 levels in liver tissues.
Additionally, the extract significantly increased Smad-7 mRNA
expression and Smad-7 and Bcl-2 protein levels in the liver
(Huang et al., 2020). These findings point to EACR being a
promising remedy for liver fibrosis. However, further studies
must be conducted urgently to identify the bioactive components
and possible mechanism of EACR’s anti-fibrotic effects (Table 2).
Cardioprotective Activity
Ventricular remodeling (VR) results in changes in endothelial
vasoactive substances, cardiomyocyte hypertrophy, myocardial
fibrosis, and endothelial dysfunction. Per Liang et al. (2020a)
investigation of the protective property of the aqueous extract of
A. carambola (AEAC) on isoprenaline-stimulated endothelial
function in rats with VR, AEAC (at daily doses of 50, 100,
and 200 mg/kg, i.g. for 14 days) glaringly lowered serum levels
of iNOS, TGF-β, Ang II, ECE, and ET-1 and their protein
expressions and decreased the VR index and CVF but
markedly elevated serum tNOS and eNOS levels and their
protein expressions. Pathological evaluations demonstrated
that AEAC radically alleviated inflammatory infiltration,
apoptosis, fibrosis, and necrosis in rat myocardial tissues,
suggesting that AEAC potentially mitigates the VR of rats and
is, therefore, possibly associated with safeguarding the balance of
vasoactive components and vascular endothelium function
(Liang et al., 2020a). Another study showed that the high-
glucose-high-fat diet combined with STZ induced the diabetes
mellitus mice model administrated with DMDD (at doses of 12.5,
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Phytochemistry and Pharmacology of Averrhoa carambola
25, and 50, 100 mg/kg/day, i.g., for 21 days) markedly alleviated
the myocardial tissues damage, inhibited the myocardial cell
apoptosis, reduced the levels of FBG, LVEDP, ROS, MDA,
Beclin-1, LC3II/I, and Atg5 as well as increased the SOD,
p-PI3K/PI3K, p-Akt/Akt, and p-mTOR/mTOR, indicating that
DMDD exerts cardioprotective activity via regulating the ROS-
mediated PI3K/Akt/mTOR autophagy pathways (Table 2; Ma
et al., 2021).
Anti-Hypertensive Activity
In Soncini et al. (2011) study of the anti-hypertensive effect of the
aqueous extract of leaves of A. carambola (AELAC) in an isolated
rat aorta and its possible mechanism, AELAC treatment (at doses
of 12.5–50.0 mg/kg, i.v.) resulted in a remarkable dose-dependent
decrease in mean arterial pressure (MAP) in normotensive rats.
In vitro, AELAC reduced Emax response to phenylephrine but
triggered no sensitivity change. AEAC also suppressed CaCl2-
stimulated aorta contractions and led to the rightward shift of the
response curves of a depolarized Ca2+-free medium, suggesting
that the extract repressed extracellular Ca2+ influx and caused
vasoconstriction. These outcomes strongly support the
traditional use of A. carambola leaves in hypertension.
Orally administered ethanol extract of A. carambola roots
(EEACR, at 150, 300, and 600 mg/kg) has been shown to lower
blood pressure in healthy rats at 300 and 600 mg/kg but have no
noticeable effect on the heart rate (Tang et al., 2017). When
Huang et al. (2017) explored the effect of flavonoids from A.
carambola fruit (FACF) on healthy rats and rats with NG-nitro-
L-arginine-methyl ester (L-NAME)-induced high blood pressure,
they established that FACF (at daily doses of 300, 600, and
1,200 mg/kg, i.g. for 5 weeks) significantly lessened systolic
blood pressure, diastolic blood pressure, and mean blood
pressure in healthy rats. Moreover, the blood pressure of rats
with hypertension was also drastically lowered by 600 and
1,200 mg/kg FAC treatments, suggesting that FACF contains
an active ingredient that decreases blood pressure (Table 2;
Huang et al., 2017).
Neuroprotective Activity
Alzheimer’s disease (AD), characterized by the progressive
deterioration of learning, memory, and cognition, is the most
common, irreversible, and progressive neurodegenerative disease
(Robins Wahlin and Byrne, 2011; Levenson et al., 2014). DMDD’s
neuroprotective effect against memory deficits and neuron apoptosis
in APP/PS1 transgenic AD mice has been reported (Wei et al., 2018).
That research showed that mice receiving DMDD (at daily doses of
12.5, 25, and 50 mg/kg for 21 days) orally displayed significantly
improved memory and spatial learning and inhibited neuron loss
and apoptosis in APP/PS1 hippocampal tissues. In vitro, DMDD (at
concentrations of 5, 10, and 20 μmol/L) radically suppressed Aβ1-
42-stimulated apoptosis by upregulating Bcl-2 expression and
downregulating Bax expression, increasing the mitochondria
membrane potential (MMP) and activating PC-12 cell caspase-3
and caspase-9. Mice pretreated with DMDD also had drastically
increased PC-12 cell Bcl-2/Bax ratio in vitro and in vivo (Wei et al.,
2018). These findings indicated that DMDD has beneficial
properties against the deficit of learning and memory in APP/
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Luan et al.
PS1 transgenic AD mice through improving neuron apoptosis and
suppressing Bax/Bcl-2-mediated loss of MMP (Table 2).
Recently, Lu et al. (2020) explored the neuroprotective activity
of DMDD against Aβ1-42-evoked SH-SY5Y cell apoptosis and the
underlying mechanism of DMDD’s protective function. Treatment
with DMDD (at concentrations of 5, 10, and 20 μmol/L)
significantly increased cell viability and inhibited Aβ1-42-
induced SH-SY5Y cell apoptosis. Mechanistically, DMDD
markedly downregulated Bax, caspase-3, caspase-8, and caspase-
9 expressions, upregulated Bcl-2 levels, suppressed the release of
cytochrome c, and the loss of MMP, and elevated the Bcl-2/Bax
ratio (Lu et al., 2020). Overall, DMDD displayed excellent
neuroprotective properties and is a promising ingredient for
developing a neuroprotective drug for Alzheimer’s disease.
Reducing Ultraviolet B-Induced Skin
Damage
Ultraviolet B (UVB) is a major causation factor of cell injury and
skin cancer. It causes DNA damage, promotes apoptosis, and
produces ROS. In Ronpirin et al. (2016) investigation of the
protective effect of A. carambola on HaCaT keratinocytes caused
by UVB, the ethanol and aqueous fractions of A. carambola
(EFAC and AFAC, at a concentration of 250 µg/ml) significantly
decreased cell apoptosis. Both fractions also ominously lowered
caspase 3 protein expression. Additionally, EFAC (at
concentrations of 100 and 250 µg/ml) and AFAC (at
concentrations of 50, 100, and 250 µg/ml) drastically reduced
the percentage of cyclobutane pyrimidine dimers (CPD),
resulting in DNA repair (Ronpirin et al., 2016). These reports
suggest that A. carambola extracts could be developed
cosmetically to protect against UVB-induced skin damage
(Table 2).
Antimicrobial Activity
The extract of the stem bark, leaves, and fruits of A. carambola
supposedly display antibacterial and antifungal activity. Previous
investigations demonstrated that the extracts of A. carambola fruits
could suppress the growth of Staphylococcus aureus and Klebsiella
spp., with the MBC of 15.62 and 125 mg/ml, respectively (Chang
et al., 2000). Moreover, two compounds p-anisaldehyde and
β-sitosterol (400 μg/disk) isolated from the bark of A. carambola
strongly inhibited the growth of Escherichia coli with a zone of
inhibition of 15 mm and had moderate inhibitory activity against
fungi (Mia et al., 2007). Afterward, Wakte and Patil (2011) screened
the antimicrobial activity of fruit extracts of star fruit at various stages
against two Gram-positive bacteria (S. aureus ATCC 6538P and B.
cereus ATCC 11778) and three Gram-negative bacteria (E. coli
ATCC 25922, P. aeruginosa ATCC 19429, and S. typhimurium
ATCC 23564), the results found that all the extracts show different
degrees of activity against Gram-positive and Gram-negative
bacteria, and the methanol and acetone extracts were
considerably more effective than other solvent extracts in
inhibiting the Gram-positive micro-organisms better than Gram
negative microorganisms. In addition, the ethanolic extracts of A.
carambola leaf at doses of 250 and 500 µg/disc were found to
moderately suppress the growth of Shigella dysenteriae, Streptococcus
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Phytochemistry and Pharmacology of Averrhoa carambola
pyogenes, Staphylococcus saprophyticus, Streptococcus agalactiae, and
Pseudomonas spp. (Hossain et al., 2017).
Recently, Silva et al. (2021) found that the extracts of stem
bark, leaves, and fruits from A. carambola perceptibly suppressed
the growth of multi-resistant pathogenic bacteria and fungi with a
minimal inhibitory concentration (MIC) of 100 μg/ml. Crude
extracts of the leaf exhibited a broad spectrum of action against
Gram-positive and Gram-negative bacteria, such as S. aureus 10
MRSA, S. aureus ATCC 29213 MRSA, S. aureus 12 MRSA, S.
aureus 6 MRSA, K. pneumoniae 8 ESBL, E. faecalis ATCC 29212,
and A. baumannii 2 MBL (Silva et al., 2021). Overall, the findings
of these studies provide a research direction that points to A.
carambola’s prospective therapeutic efficacy against bacterial and
fungal infections.
TOXICITY ASSESSMENT
Literature material on the assessment of the toxicity and safety of
A. carambola is limited, although this plant is commonly utilized
in TCM to treat numerous ailments. In recent years, several
studies have found that the excessive consumption of A.
carambola results in toxic effects. Aranguren et al. (2017)
literature review revealed that 123 patients from eight nations
developed acute renal injury after consuming this fruit. Forty-
seven of the cases were registered in Brazil, the highest reported
incidence, followed by Taiwan (36), Bangladesh (20), China and
France (8 each), Sri Lanka (2), and Thailand and Colombia (1
each); 28 of the patients died. In the most recent investigation,
Yasawardene et al. (2021) analyses of 10 case series and 28 case
reports in humans (total number of individuals  136) and eight
animal studies for A. carambola nephrotoxicity and
neurotoxicity, 94 (69.1%) patients had prior renal impairment,
with renal histology revealing acute oxalate nephropathy with
tubulointerstitial nephritis or tubular necrosis. Also,
neurotoxicity performances ranged from hiccups to status
epilepticus. The excessive uptake of A. carambola could lead
to acute kidney injury, particularly in an empty stomach, or
dehydration state, and the use of A. carambola as therapy for an
elderly patient is not recommended on an empty stomach
(Wijayaratne et al., 2018). In addition, A. carambola has
threatened people’s health despite the relatively low frequency
of star fruit intake. Further clinical studies on the toxic
ingredients, metabolites, and intake dose of star fruit toxicity
must be carried out to provide clear indications of intake and
prevent toxicity and mortality.
The results of animal experiments showed that the high
dose of the different A. carambola extracts showed different
degrees of toxicity or adverse reactions. Chen et al. (2001)
found that an overdose intake of the fruit could result in
nephrotoxicity and neurotoxicity in some individuals (Chen
et al., 2001). Supposedly, the fruit of A. carambola could
cause fatality in patients suffering from uremia, with oxalate
identified as being a significant element in the toxicity of the
fruit (Dembitsky et al., 2011). Furthermore, an acute toxicity
study conducted in female albino rats revealed that oral
administration of A. carambola juice extract (ACJE) at
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Luan et al.
different doses (250, 500, 1,000, 2000, 4,000, and
5,000 mg/kg) was safe and did not lead to any poisonous
reactions after 48 h of treatment, despite the dosage reaching
up to 5,000 mg/kg. In the subacute evaluations, oral ACJE (at
dosages of 200, 400, and 600 mg/kg for 28 consecutive days)
treatment elicited no significant difference in total protein,
albumin, hematological parameters, and globulin values
between treatment-receiving and control groups. However,
serum AST, ALT, and ALP levels and urea, creatinine, and
MDA levels in the treat-receiving group dose-dependently
increased significantly more than in the control group.
Moreover, when compared with the control group, the
histomorphology of the livers and kidneys of the rats
treated with ACJE displayed lesions of degeneration and
necrosis (Aba and Amadi, 2019). Recent investigations
systematically revealed that the nephrotoxic effect of A.
carambola stems primarily from oxalate deposition in
renal tubules, causing interstitial nephritis and acute
tubular necrosis (Yasawardene et al., 2020). These results
indicate that excessive and long-term consumption of ACJE
could be nephrotoxic and hepatotoxic. Therefore, it is very
important to study the intake dose as well as effective and safe
dose in the future.
Phytochemical studies have shown that A. carambola contains
two poisonous substances, caramboxin, and oxalic acid.
Caramboxin is a non-proteinogenic amino acid that stimulates
the glutamate receptors in neurons. The chemical structure of
caramboxin is similar to the amino acid phenylalanine, it is
metabolized and excreted through the kidneys (Yasawardene
et al., 2020). Caramboxin can effectively stimulate the central
nervous system (CNS), resulting in symptoms of CNS disorder,
including mental confusion, seizures, and status epilepticus
(Yasawardene et al., 2020). It can cause belch, vomiting,
confusion, consciousness disorders, and shock, etc. If normal
people eat this fruit, caramboxin can be safely discharged, so
normal people will not be damaged by the toxin when it is
ingested. However, the patients with renal insufficiency,
especially in patients undergoing peritoneal dialysis or
hemodialysis can’t eat it. Huynh and Nguyen (2017) findings
showed that the alcohol fermentation technologies efficaciously
reduced oxalate contents in A. carambola, preventing the risk of
kidney stone formation. However, the works on the dose of
caramboxin and the bioavailability of oxalate and caramboxin
after ingestion are still insufficient, and more comprehensive,
systematic, and authentic studies are required to assess the dose of
caramboxin of star fruit juice and its pharmacokinetic parameters
in healthy individuals.
FUTURE OUTLOOKS
This review summarized the botany, ethnopharmacology,
phytochemistry, pharmacology, and toxicity of A. carambola
to explore this valuable fruit. The succulence and sweet taste
of starfruit are of interest to the food industry. The
pharmaceutical and health industries have been increasingly
interested in A. carambola due to the nutritional properties as
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Phytochemistry and Pharmacology of Averrhoa carambola
well as various health and pharmacological actions of this fruit.
Phytochemical investigations have shown that 132 compounds
have been mainly reported from A. carambola. The flavonoids
represented by compounds 47 and 48 and benzoquinones
represented by DMDD have been considered as the
biologically active components with extensive biological
properties, including anti-hyperglycemic, anti-hyperlipidemic,
anti-obesity, anti-inflammatory, hepatoprotective, anti-tumor,
cardioprotective, and neuroprotective activities. Numerous
studies have revealed that A. carambola might be a promising
candidate to treat diabetes mellitus and DN-related diseases.
Furthermore, A. carambola can be employed in the prevention
and treatment of ailments related to aging and oxidative stress. In
summary, A. carambola, as a food and medicinal resource, has a
good health care function and important edible and medicinal
value, and thus has good prospects for utilization.
There are nevertheless still many problems in research that
aims to bridge the gap between health and the bioactive
substances of A. carambola, which need to be studied
further: firstly, although there are a large number of in vitro
and in vivo studies concentrated on the crude extracts of A.
carambola using exorbitant doses, to the best of our
knowledge, the active substances from these crude extracts
with bioactivities are still unknown. Thus, research aiming to
clarify the biological activities and the mechanism of active
components found in A. carambola should be clearly
conducted in further depth, as they will certainly
collaborate to the establishment of safe dosages and
accelerate the steps for the discovery of new molecules of
biological interest. Secondly, the bioactive compounds and
crude extracts of A. carambola have been increasingly and
successfully utilized in diabetic disease prevention and health
promotion in the last few decades. The documentary evidence
points to a high number of bioactive compounds and crude
extracts in star fruit that might be used as functional food
sources against various illnesses including diabetes, cancer,
cardiovascular disease, and other oxidative stresses or aging-
induced chronic diseases. There is a need for further research
to explore and utilize the processed products of this fruit,
especially those phenolic extracts and dietary fibers in A.
carambola for functional food formulation. Thirdly,
although toxicity studies of A. carambola have been
reported, the information related to its toxicity mechanism,
especially nephrotoxicity and neurotoxicity, is still lacking. It is
reported that A. carambola induced oxalate nephropathy
remains an under-recognized cause for both acute and
chronic kidney disease. Therefore, more public awareness
about oxalate poisoning on uremic patients should be
promoted. This will help to avoid adverse reactions to star-
fruits in high uremic patients. The public must be well
educated on the benefits as well as the hazardous effects of
star fruits. Furthermore, toxicological studies are crucial for
understanding the safety of herbal drugs. Therefore, to ensure
the full use of its medicinal resources, further acute toxicity,
and subacute toxicity, as well as the safety assessment studies
of A. carambola, both in vitro and in vivo, should be carried
out. Fourthly, continued efforts will be needed to clarify the
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Luan et al.
pathways of pharmacokinetics including absorption,
distribution, metabolism, and excretion, and to assess the
long-term chronic toxicity and acute toxicity as well as the
metabolites of phytochemicals formed in vivo of the bioactive
compounds, especially for DMDD before proceeding to the
development of pharmaceutical formulation. The
pharmacokinetics parameters also contribute to facilitate the
rational optimization of natural active substances, and
increase therapeutic effects and reduce toxicities. Overall,
in-depth research on clinical studies to justify their reported
therapeutic potential, clinical efficacy, and safety of A.
carambola is imminent.
Taken together, significant interest has been generated over A.
carambola owing to the numerous beneficial effects. A. carambola
appears to have great developing potential in the fields of
functional food and modern medicine. Therefore, the
opportunities and challenges co-exist. Meanwhile, it is an
effective approach for TCM to get into the international
market and an ideal choice for modern health care in
developed countries for ongoing human health and thereby
building a healthy community with a shared future for
mankind. We believe that A. carambola will have an extensive
international market and a broad prospect in terms of its
applications in both medicine and functional food.
REFERENCES
Aba, P. E., and Amadi, A. U. (2020). Evaluation of the Possible Hepatotoxic and
Nephrotoxic Potentials of the Averrhoa carambola Juice Extract in Female Albino
Rats. J. Basic Clin. Physiol. Pharmacol. 31 (1), 20190042. doi:10.1515/jbcpp-2019-
0042
Abeysekera, R. A., Wijetunge, S., Nanayakkara, N., Wazil, A. W., Ratnatunga, N.
V., Jayalath, T., et al. (2015). Star Fruit Toxicity: a Cause of Both Acute Kidney
Injury and Chronic Kidney Disease: a Report of Two Cases. BMC Res. Notes 8,
796. doi:10.1186/s13104-015-1640-8
Aladaileh, S., Saghir, S., Murugesu, K., Sadikun, A., Ahmad, A., Kaur, G., et al.
(2019). Antihyperlipidemic and Antioxidant Effects of Averrhoa Carambola
Extract in High-Fat Diet-Fed Rats. Biomedicines 7 (3), 72. doi:10.3390/
biomedicines7030072
Araho, D., Miyakoshi, M., Chou, W. H., Kambara, T., Mizutani, K., and Ikeda, T.
(2005). A New Flavone C-Glycoside from the Leaves of Averrhoa Carambola.
Nat. Med. 59, 113–116. doi:10.1016/j.apsusc.2004.03.089
Aranguren, C., Vergara, C., and Rosselli, D. (2017). Toxicity of Star Fruit (Averrhoa
carambola) in Renal Patients: A Systematic Review of the Literature. Saudi
J. Kidney Dis. Transpl. 28 (4), 709–715.
Bahramsoltani, R., Kalkhorani, M., Abbas Zaidi, S. M., Farzaei, M. H., and Rahimi,
R. (2020). The Genus Tamarix: Traditional Uses, Phytochemistry, and
Pharmacology. J. Ethnopharmacol. 246, 112245. doi:10.1016/j.jep.2019.112245
Benkeblia, N., and Lopez, M. G. (2015). Saccharides and Fructooligosaccharides
Composition of Green and Ripe Averrhoa carambola, Blighia sapida and Spondias
dulcis Fruits. Food Chem. 176, 314–318. doi:10.1016/j.foodchem.2014.12.080
Bhat, R., Ameran, S. B., Voon, H. C., Karim, A. A., and Tze, L. M. (2011). Quality
Attributes of Starfruit (Averrhoa carambola L.) Juice Treated with Ultraviolet
Radiation. Food Chem. 127 (2), 641–644. doi:10.1016/j.foodchem.2011.01.042
Bircher, A. G., and Bircher, W. H. (2000). Encyclopedia of Fruit Trees and Edible
Flowering Plants in Egypt and the Subtropics. Cairo, Egypt: American University
in Cairo Press, 596.
Cabrini, D. A., Moresco, H. H., Imazu, P., da Silva, C. D., Pietrovski, E. F., Mendes,
D. A., et al. (2011). Analysis of the Potential Topical Anti-inflammatory
Activity of Averrhoa carambola L. in Mice. Evid. Based Complement.
Alternat Med. 2011, 908059. doi:10.1093/ecam/neq026
Frontiers in Pharmacology | www.frontiersin.org
Phytochemistry and Pharmacology of Averrhoa carambola
AUTHOR CONTRIBUTIONS
FL obtained the literatures, wrote the manuscript, and finalized
the paper. LP and ZL arranged the tables and designed the figures,
XJ collected the pictures. JZ, YY, and XH retrieved relevant
literature and discussed the manuscript layout. NZ and XH
designed and revised the manuscript, checked the accuracy,
and edited the final version. All authors read and approved
the final version of the manuscript for publication.
FUNDING
This study was financially supported by the National Natural
Science Foundation of China (Grant No. 82074094), the Open
Research Fund of Chengdu University of Traditional Chinese
Medicine Key Laboratory of Systematic Research of Distinctive
Chinese Medicine Resources in Southwest China (Grant No.
2020XSGG002), the Xinglin Scholar Research Promotion
Project of Chengdu University of Traditional Chinese Medicine
(Grant No. CDTD2018014), the Science and Technology Plan
Project of Guizhou Province (Grant No. Qian KeHe Platform
Talents (2018)5772-074), and the Science and Technology Project
of Zunyi (Grant No. ZSKH-HZ-(2020)-78).
Carolino, R., Beleboni, R., Pizzo, A., Vecchio, F., Garciacairasco, N., Moysesneto,
M., et al. (2005). Convulsant Activity and Neurochemical Alterations Induced
by a Fraction Obtained from Fruit (Oxalidaceae: Geraniales). Neurochem. Int.
46 (7), 523–531. doi:10.1016/j.neuint.2005.02.002
Cazarolli, L. H., Folador, P., Moresco, H. H., Brighente, I. M. C., Pizzolatti, M. G.,
and Silva, F. R. M. B. (2009). Mechanism of Action of the Stimulatory Effect of
Apigenin-6-C-(2″-O-α-l-Rhamnopyranosyl)-β-L-Fucopyranoside on 14C-
Glucose Uptake. Chem. Biol. Interact. 179, 407–412. doi:10.1016/
j.cbi.2008.11.012
Cazarolli, L. H., Kappel, V. D., Pereira, D. F., Moresco, H. H., Brighente, I. M. C.,
Pizzolatti, M. G., et al. (2012). Anti-hyperglycemic Action of Apigenin-6-C-
β-Fucopyranoside from Averrhoa Carambola. Fitoterapia 83, 1176–1183.
doi:10.1016/j.fitote.2012.07.003
Chakthong, S., Chiraphan, C., Jundee, C., Chaowalit, P., and Voravuthikunchai, S.
P. (2010). Alkyl Phenols from the wood of Averrhoa Carambola. Chin. Chem.
Lett. 21, 1094–1096. doi:10.1016/j.cclet.2010.03.031
Chang, J. M., Hwang, S. J., Kuo, H. T., Tsai, J. C., Guh, J. Y., Chen, H. C., et al.
(2000). Fatal Outcome after Ingestion of Star Fruit (Averrhoa carambola) in
Uremic Patients. Am. J. Kidney Dis. 35 (2), 189–193. doi:10.1016/s0272-
6386(00)70325-8
Chen, C. L., Fang, H. C., Chou, K. J., Wang, J. S., and Chung, H. M. (2001). Acute
Oxalate Nephropathy after Ingestion of star Fruit. Am. J. Kidney Dis. 37 (2),
418–422. doi:10.1053/ajkd.2001.21333
Chen, C. X., Nong, Z. H., Xie, Q. Q., He, J. H., Cai, W. E., Tang, X. N., et al. (2017b).
2-dodecyl-6-Methoxycyclohexa-2,5-Diene-1,4-Dione Inhibits the Growth and
Metastasis of Breast Carcinoma in Mice. Sci. Rep. 7 (1), 6704. doi:10.1038/
s41598-017-07162-3
Chen, G. L., Zhang, X., Chen, S. G., Han, M. D., and Gao, Y. Q. (2017a).
Antioxidant Activities and Contents of Free, Esterified and Insoluble-Bound
Phenolics in 14 Subtropical Fruit Leaves Collected from the South of China.
J. Funct. Foods 30, 290–302. doi:10.1016/j.jff.2017.01.011
Chen, L., Lu, X., El-Seedi, H., and Teng, H. (2019). Recent Advances in
the Development of Sesquiterpenoids in the Treatment of Type 2
Diabetes. Trends Food Sci. Technol. 88, 46–56. doi:10.1016/
j.tifs.2019.02.003
Chua, C. B., Sun, C. K., Tsui, H. W., Yang, P. J., Lee, K. H., Hsu, C. W., et al. (2017).
Association of Renal Function and Symptoms with Mortality in star Fruit
23 August 2021 | Volume 12 | Article 699899
Luan et al.
(Averrhoa carambola) Intoxication. Clin. Toxicol. 55 (7), 624–628. doi:10.1080/
15563650.2017.1314490
Dembitsky, V. M., Poovarodom, S., Leontowicz, H., Leontowicz, M., Vearasilp, S.,
Trakhtenberg, S., et al. (2011). The Multiple Nutrition Properties of Some
Exotic Fruits: Biological Activity and Active Metabolites. Food Res. Int. 44,
1671–1701. doi:10.1016/j.foodres.2011.03.003
Fan, Y. Y., Sahu, S. K., Yang, T., Mu, W. X., Wei, J. P., Cheng, L., et al. (2020).
Dissecting the Genome of star Fruit (Averrhoa carambola L.). Hortic. Res. 7, 94.
doi:10.1038/s41438-020-0306-4
Farias, D. P., Neri-Numa, I. A., de Araújo, F. F., and Pastore, G. M. (2020). A
Critical Review of Some Fruit Trees from the Myrtaceae Family as Promising
Sources for Food Applications with Functional Claims. Food Chem. 306,
125630. doi:10.1016/j.foodchem.2019.125630
Ferreira, E. B., Fernandes, L. C., Galende, S. B., Cortez, A. G., and Bazotte, R. B.
(2008). Hypoglycemic Effect of the Hydroalcoholic Extract of Leaves of
Averrhoa carambola L. (Oxalidaceae). Rev. Bras. Farmacogn. 18 (3),
339–343. doi:10.1590/s0102-695x2008000300005
Flora of China Editorial Committee (1998). Flora of China. Beijing, China: Science
Press.
Gao, Y., Huang, R., Gong, Y., Park, H. S., Wen, Q., Almosnid, N. M., et al. (2015).
The Antidiabetic Compound 2-Dodecyl-6-Methoxycyclohexa-2,5-Diene-1,4-
Dione, Isolated from Averrhoa carambola L., Demonstrates Significant
Antitumor Potential against Human Breast Cancer Cells. Oncotarget 6 (27),
24304–24319. doi:10.18632/oncotarget.4475
Gunasegaran, R. (1992). Flavonoids and Anthocyanins of Three Oxalidaceae.
Fitoterapia 63, 89–90 .
Gunawardena, D. C., Jayasinghe, L., and Fujimoto, Y. (2015). Phytotoxic
Constituents of the Fruits of Averrhoa Carambola. Chem. Nat. Compd. 51
(3), 532–533. doi:10.1007/s10600-015-1332-6
Herman-Lara, E., Elvira-Torales, L. I., Rodriguez-Miranda, J., Torruco-Uco, J. G.,
Carmona-García, R., Mendoza-García, P. G., et al. (2014). Impact of
Micronized Starfruit (Averrhoa carambola L.) Fiber Concentrate on Lipid
Metabolism in Mice. Int. J. Food Sci. Nutr. 65 (7), 862–867. doi:10.3109/
09637486.2014.918590
Hossain, T., Barman, A. K., Karmakar, U. K., Bokshi, B., Dev, S., and Biswas, N. N.
(2017). Phytochemical and Pharmacological Evaluation of Leaves of Averrhoa
carambola Linn. (Family: Oxalidaceae). Biosci. Bioeng. Commun. 3 (1), 144–151.
Huang, W. S., Pham, H. T. T., Xuan, F. F., Li, J. M., and Huang, R. B. (2017). Effects
of Flavonoids Compound in Averrhoa carambola L. (Oxalidacaeae) Fruit
(ACFTF) on Blood Pressure of Rats. China J. Tradit. Chin. Med. Pharm. 32
(4), 1786–1788.
Huang, X., Wang, L., Meng, M., Zhang, S., Pham, T. T. H., Jiang, L., et al. (2020).
Extract of Averrhoa carambola L. (Oxalidaceae) Roots Ameliorates Carbon
Tetrachloride-Induced Hepatic Fibrosis in Rats. Biomed. Pharmacother. 121,
109516. doi:10.1016/j.biopha.2019.109516
Huang, X., Xie, Q. Q., Ye, F. X., Qin, L. H., Huang, R. B., and Zhang, S. J. (2019).
Protective Effect of Extract of Averrhoa carambola L. Root on CCl4-Induced
Acute Liver Injury in Mice. Chin. Pharmacol. Bull. 35 (1), 106–110. doi:10.3969/
j.issn.1001-1978.2019.01.021
Huynh, N. K., and Nguyen, H. V. H. (2017). Effects of Juice Processing on Oxalate
Contents in Carambola Juice Products. Plant Foods Hum. Nutr. 72 (3),
236–242. doi:10.1007/s11130-017-0615-4
Islam, S., Alam, M. B., Ahmed, A., Lee, S., Lee, S.-H., and Kim, S. (2020).
Identification of Secondary Metabolites in Averrhoa carambola L. Bark by
High-Resolution Mass Spectrometry and Evaluation for α-glucosidase,
Tyrosinase, Elastase, and Antioxidant Potential. Food Chem. 332, 127377.
doi:10.1016/j.foodchem.2020.127377
Jayachandran, M., and Qu, S. (2021). Harnessing Hyperuricemia to Atherosclerosis
and Understanding its Mechanistic Dependence. Med. Res. Rev. 41, 616–629.
doi:10.1002/med.21742
Jia, X., Xie, H., Jiang, Y., and Wei, X. (2018). Flavonoids Isolated from the Fresh
Sweet Fruit of Averrhoa Carambola , Commonly Known as star Fruit.
Phytochemistry 153, 156–162. doi:10.1016/j.phytochem.2018.06.007
Jia, X., Yang, D., Xie, H., Jiang, Y., and Wei, X. (2017). Non-Flavonoid Phenolics from
Averrhoa carambola Fresh Fruit. J. Funct. Foods 32, 419–425. doi:10.1016/j.jff.2017.03.025
Jia, X., Yang, D., Yang, Y., and Xie, H. (2019). Carotenoid-Derived Flavor
Precursors from Averrhoa carambola Fresh Fruit. Molecules 24, 256.
doi:10.3390/molecules24020256
Frontiers in Pharmacology | www.frontiersin.org
Phytochemistry and Pharmacology of Averrhoa carambola
Lakmal, K., Yasawardene, P., Jayarajah, U., and Seneviratne, S. L. (2021).
Nutritional and Medicinal Properties of Star Fruit (Averrhoa carambola L.):
A Review. Food Sci. Nutr. 9 (3), 1810–1823. doi:10.1002/fsn3.2135
Leivas, C. L., Iacomini, M., and Cordeiro, L. M. C. (2016b). Pectic Type II
Arabinogalactans from Starfruit (Averrhoa carambola L.). Food Chem. 199,
252–257. doi:10.1016/j.foodchem.2015.12.020
Leivas, C. L., Iacomini, M., and Cordeiro, L. M. C. (2015). Structural
Characterization of a Rhamnogalacturonan I-Arabinan-Type I
Arabinogalactan Macromolecule from Starfruit (Averrhoa carambola L).
Carbohydr. Polym. 121, 224–230. doi:10.1016/j.carbpol.2014.12.034
Leivas, C. L., Nascimento, L. F., Barros, W. M., Santos, A. R. S., Iacomini, M., and
Cordeiro, L. M. C. (2016a). Substituted Galacturonan from Starfruit: Chemical
Structure and Antinociceptive and Anti-Inflammatory Effects. Int. J. Biol.
Macromol. 84, 295–300. doi:10.1016/j.ijbiomac.2015.12.034
Levenson, R. W., Sturm, V. E., and Haase, C. M. (2014). Emotional and Behavioral
Symptoms in Neurodegenerative Disease: a Model for Studying the Neural
Bases of Psychopathology. Annu. Rev. Clin. Psychol. 10, 581–606. doi:10.1146/
annurev-clinpsy-032813-153653
Li, J., Wei, X., Xie, Q., Hoa Pham, T. T., Wei, J., He, P., et al. (2016). Protective
Effects of 2-Dodecyl-6-Methoxycyclohexa-2,5 -Diene-1,4-Dione Isolated from
Averrhoa Carambola L. (Oxalidaceae) Roots on High-Fat Diet-Induced Obesity
and Insulin Resistance in Mice. Cell. Physiol. Biochem. 40 (5), 993–1004.
doi:10.1159/000453156
Liang, C. X., Pham, H. T. T., Zhang, X. L., Liang, X. M., Huang, R. B., and Huang, X.
(2020b). Effect of Extract of Averrhoa carambola L. Root on Liver
Microstructure of Liver Fibrosis Rats. J. Guangxi Med. Univ. 37 (7),
1245–1249. doi:10.16190/j.cnki.45-1211/r.2020.07.008
Liang, X., Huang, R., Huang, J., Chen, C., Qin, F., Liu, A., et al. (2020a). Effect of an
Aqueous Extract of Averrhoa carambola L. on Endothelial Function in Rats
with Ventricular Remodelling. Biomed. Pharmacother. 121, 109612.
doi:10.1016/j.biopha.2019.109612
Liao, P. Y., Li, D. P., Hu, Z. Y., Chen, H. P., Yang, X. M., and Wu, Y. Y. (2019b).
Extraction Process Optimization and In Vitro Activity Evaluation for
Polysaccharides from Averrhoa carambola Roots. Chin. Tradit. Pat. Med. 41
(9), 2030–2034. doi:10.3969/j.issn.1001-1528.2019.09.002
Liao, P. Y., Zhou, Z. Y., Chen, Y. R., Chen, H. P., Pan, W. G., Yang, X. M., et al.
(2019a). Chemical Constituents of the Water Extracts of Averrhoa carambola L.
Root and Their Biological Activities. Nat. Prod. Res. Dev. 31, 81–86.
doi:10.16333/j.1001-6880.2019.1.013
Liu, F. Z., Song, X. M., Wang, X. L., Liu, T., and Liang, R. F. (2013). Hypoglycemic
Effect of Total Flavones from Averrhoa carambola L. Leaf. China J. Tradit. Chin.
Med. Pharm. 19 (11), 279–281.doi:10.11653/syfj2013110279
Lu, S. Y., Wei, X. J., Zhang, H. L., Chen, Z. F., Li, J. M., Xu, X. H., et al. (2020).
Protective Effect of 2-Dodecyl-6-Methoxycyclohexa-2, 5-Diene-1, 4-Dione,
Isolated from Averrhoa carambola L., Against Aβ1-42-Induced Apoptosis in
SH-SY5Y Cells by Reversing Bcl-2/Bax Ratio. Psychopharmacology 238 (1),
193–200. doi:10.1007/s00213-020-05668-9
Lu, S., Zhang, H., Wei, X., Huang, X., Chen, L., Jiang, L., et al. (2019). 2-Dodecyl-6-
Methoxycyclohexa-2,5-Diene-1,4-Dione Isolated from Averrhoa carambola L.
Root Ameliorates Diabetic Nephropathy by Inhibiting the TLR4/MyD88/NF-Κb
Pathway. Diabetes Metab. Syndr. Obes. 12, 1355–1363. doi:10.2147/dmso.s209436
Lu, Y., Tan, C. W., Chen, D., and Liu, S.-Q. (2018). Potential of Three Probiotic
Lactobacilli in Transforming Star Fruit Juice into Functional Beverages. Food
Sci. Nutr. 6 (8), 2141–2150. doi:10.1002/fsn3.775
Ma, J., Wu, Y. N., Huang, D. L., Zhou, Y. P., Hou, L. T., Li, Y. K., et al. (2021).
Averrhoa carambola L. Roots DMDD Alleviates Myocardial Injury in Diabetes
Mellitus Mice by Regulating ROS-Mediated Autophagy Pathways. Chin.
Pharmacol. Bull. 37 (6), 823–827. doi:10.3969/j.issn.1001-1978.2021.06.015
Mahdavi, A., Bagherniya, M., Fakheran, O., Reiner, Ž., Xu, S., and Sahebkar, A.
(2020). Medicinal Plants and Bioactive Natural Compounds as Inhibitors of
HMG-CoA Reductase: A Literature Review. Biofactors 46, 906–926.
doi:10.1002/biof.1684
Maqsood, S., Adiamo, O., Ahmad, M., and Mudgil, P. (2020). Bioactive Compounds
from Date Fruit and Seed as Potential Nutraceutical and Functional Food
Ingredients. Food Chem. 308, 125522. doi:10.1016/j.foodchem.2019.125522
Mia, M., Rahman, M., Begum, K., Begum, B., and Rashid, M. (2007).
Phytochemical and Biological Studies of Averrhoa carambola. Dhaka Univ.
J. Pharm. Sci. 6, 125–128. doi:10.3329/dujps.v6i2.688
24 August 2021 | Volume 12 | Article 699899
Luan et al.
Mohd Suhaimi, N. I., Mat Ropi, A. A., and Shaharuddin, S. (2021). Safety and
Quality Preservation of Starfruit (Averrhoa carambola) at Ambient Shelf Life
Using Synergistic Pectin-Maltodextrin-Sodium Chloride Edible Coating.
Heliyon 7 (2), e06279. doi:10.1016/j.heliyon.2021.e06279
Moresco, H. H., Queiroz, G. S., Pizzolatti, M. G., and Brighente, I. M. C. (2012).
Chemical Constituents and Evaluation of the Toxic and Antioxidant Activities
of Averrhoa carambola Leaves. Rev. Bras. Farmacogn. 22, 319–324. doi:10.1590/
s0102-695x2011005000217
Muhammed, E., Chen, L., Gao, Y., and Erenso, D. (2019). Chemo-Treated 4T1
Breast Cancer Cells Radiation Response Measured by Single and Multiple Cell
Ionization Using Infrared Laser Trap. Sci. Rep. 9 (1), 17547. doi:10.1038/
s41598-019-53821-y
Muthu, N., Lee, S. Y., Lee, S. Y., Phua, K. K., and Bhore, S. J. (2016). Nutritional,
Medicinal and Toxicological Attributes of Star-Fruits (Averrhoa carambola L.):
A Review. Bioinformation 12 (12), 420–424. doi:10.6026/97320630012420
Pang, D., You, L., Li, T., Zhou, L., Sun-Waterhouse, D., and Liu, R. H. (2016). Phenolic
Profiles and Chemical- or Cell-Based Antioxidant Activities of Four Star Fruit
(Averrhoa carambola) Cultivars. RSC Adv. 6, 90646–90653. doi:10.1039/c6ra15692d
Pang, D., You, L., Zhou, L., Li, T., Zheng, B., and Liu, R. H. (2017). Averrhoa Carambolafree
Phenolic Extract Ameliorates Nonalcoholic Hepatic Steatosis by Modulating
mircoRNA-34a, mircoRNA-33 and AMPK Pathways in Leptin Receptor-Deficient
db/db Mice. Food Funct. 8 (12), 4496–4507. doi:10.1039/c7fo00833c
Pham, H. T., Huang, W., Han, C., Li, J., Xie, Q., Wei, J., et al. (2017). Effects of Averrhoa
carambola L. (Oxalidaceae) Juice Mediated on Hyperglycemia, Hyperlipidemia, and
its Influence on Regulatory Protein Expression in the Injured Kidneys of
Streptozotocin-Induced Diabetic Mice. Am. J. Transl. Res. 9 (1), 36–49.
Provesi, J. G., Valentim Neto, P. A., Arisi, A. C. M., and Amante, E. R. (2019).
Extraction of Antifreeze Proteins from Cold Acclimated Leaves of Drimys
Angustifolia and Their Application to star Fruit (Averrhoa carambola)
Freezing. Food Chem. 289, 65–73. doi:10.1016/j.foodchem.2019.03.055
Qin, L. H., Wu, X. C., Zhou, X., Wu, Y. N., Huang, R. B., and Zhang, S. J. (2019).
Effects of Benzoquinone of Averrhoa carambola L. Root on Glucose and Lipid
Metabolism, Oxidative Stress and Inflammatory Injury in Diabetic Mice. Chin.
Pharmacol. Bull. 35 (12), 1720–1725. doi:10.3969/j.issn.1001-1978.2019.12.019
Qin, L., Zhang, X., Zhou, X., Wu, X., Huang, X., Chen, M., et al. (2020). Protective
Effect of Benzoquinone Isolated from the Roots of Averrhoa carambola L. on
Streptozotocin-Induced Diabetic Mice by Inhibiting the TLR4/NF-κB Signaling
Pathway. Diabetes Metab. Syndr. Obes. 13, 2129–2138. doi:10.2147/dmso.s241998
Ramadan, N. S., Wessjohann, L. A., Mocan, A., C Vodnar, D., H. El-Sayed, N., A.
El-Toumy, S., et al. (2020). Nutrient and Sensory Metabolites Profiling of
Averrhoa carambola L. (Starfruit) in the Context of its Origin and Ripening
Stage by GC/MS and Chemometric Analysis. Molecules 25 (10), 2423.
doi:10.3390/molecules25102423
Rashid, A. M., Lu, K., Yip, Y. M., and Zhang, D. (2016). Averrhoa carambola L. Peel
Extract Suppresses Adipocyte Differentiation in 3T3-L1 Cells. Food Funct. 7 (2),
881–892. doi:10.1039/c5fo01208b
Robins Wahlin, T.-B., and Byrne, G. J. (2011). Personality Changes in Alzheimer’s
Disease: a Systematic Review. Int. J. Geriat. Psychiatry 26 (10), 1019–1029.
doi:10.1002/gps.2655
Ronpirin, C., Pattarachotanant, N., and Tencomnao, T. (2016). Protective
Effect of Mangifera indica Linn., Cocos nucifera Linn., and Averrhoa
carambola Linn. Extracts against Ultraviolet B-Induced Damage in
Human Keratinocytes. Evid. Based Compl. Alternat. Med. 2016,
1684794. doi:10.1155/2016/1684794
Rufino, M. S. M., Alves, R. E., Fernandes, F. A. N., and Brito, E. S. (2011). Free
Radical Scavenging Behavior of Ten Exotic Tropical Fruits Extracts. Food Res.
Int. 44 (7), 2072–2075. doi:10.1016/j.foodres.2010.07.002
Saghir, S. A., Sadikun, A., Al-Suede, F. S., Majid, A. M., and Murugaiyah, V. (2016).
Antihyperlipidemic, Antioxidant and Cytotoxic Activities of Methanolic and
Aqueous Extracts of Different Parts of Star Fruit. Curr. Pharm. Biotechnol. 17
(10), 915–925. doi:10.2174/1389201017666160603013434
Saikia, S., Mahnot, N. K., and Mahanta, C. L. (2015). Optimisation of Phenolic
Extraction from Averrhoa carambola Pomace by Response Surface
Methodology and its Microencapsulation by spray and Freeze Drying. Food
Chem. 171, 144–152. doi:10.1016/j.foodchem.2014.08.064
Shui, G., and Leong, L. P. (2004). Analysis of Polyphenolic Antioxidants in star
Fruit Using Liquid Chromatography and Mass Spectrometry. J. Chromatogr. A
1022, 67–75. doi:10.1016/j.chroma.2003.09.055
Frontiers in Pharmacology | www.frontiersin.org
Phytochemistry and Pharmacology of Averrhoa carambola
Shui, G., and Leong, L. P. (2006). Residue from star Fruit as Valuable Source for
Functional Food Ingredients and Antioxidant Nutraceuticals. Food Chem. 97,
277–284. doi:10.1016/j.foodchem.2005.03.048
Siddika, A., Zahan, T., Khatun, L., Habib, M. R., Aziz, M. A., Tareq, A. R. M., et al.
(2020). In Vivo the Antioxidative Extract of Averrhoa carambola Linn. Leaves
Induced Apoptosis in Ehrilch Ascites Carcinoma by Modulating P53 Expression.
Food Sci. Biotechnol. 29 (9), 1251–1260. doi:10.1007/s10068-020-00775-x
Silva, K. B., Pinheiro, C. T. S., Soares, C. R. M., Souza, M. A., Matos-Rocha, T. J., Fonseca, S.
A., et al. (2021). Phytochemical Characterization, Antioxidant Potential and
Antimicrobial Activity of Averrhoa carambola L. (Oxalidaceae) against
Multiresistant Pathogens. Braz. J. Biol. 81 (3), 509–515. doi:10.1590/1519-6984.220259
Silva, K. D. R. R., and Sirasa, M. S. F. (2018). Antioxidant Properties of Selected
Fruit Cultivars Grown in Sri Lanka. Food Chem. 238, 203–208. doi:10.1016/
j.foodchem.2016.08.102
Singh, R., Sharma, J., and Goyal, P. K. (2014). Prophylactic Role of Averrhoa carambola
(Star Fruit) Extract against Chemically Induced Hepatocellular Carcinoma in Swiss
Albino Mice. Adv. Pharmacol. Sci. 2014, 158936. doi:10.1155/2014/158936
Soncini, R., Santiago, M. B., Orlandi, L., Moraes, G. O. I., Peloso, A. L. M., dos
Santos, M. H., et al. (2011). Hypotensive Effect of Aqueous Extract of Averrhoa
carambola L. (Oxalidaceae) in Rats: an In Vivo and In Vitro Approach.
J. Ethnopharmacol. 133 (2), 353–357. doi:10.1016/j.jep.2010.10.001
Sritharan, T., Savitri Kumar, N., Jayasinghe, L., Araya, H., and Fujimoto, Y. (2019).
Isocoumarins and Dihydroisocoumarins from the Endophytic Fungus
Biscogniauxia capnodes Isolated from the Fruits of Averrhoa carambola. Nat.
Product. Commun. 14, 1934578X1985196. doi:10.1177/1934578X19851969
Tang, J. Z., Nong, H. L., Liang, X. M., Huang, J. C., Qin, F. Z., and Huang, R. B.
(2017). Effect of the Ethanol Extracts of Averrhoa carambola Root on Blood
Pressure in Normal Rats. West. China J. Pharm. Sci. 32 (2), 160–162.
doi:10.1016/j.biopha.2019.109612
Teng, H., Yuan, B., Gothai, S., Arulselvan, P., Song, X., and Chen, L. (2018). Dietary
Triterpenes in the Treatment of Type 2 Diabetes: To Date. Trends Food Sci.
Technol. 72, 34–44. doi:10.1016/j.tifs.2017.11.012
Thomas, R., Jebin, N., Saha, R., and Sarma, D. K. (2016). Antioxidant and
Antimicrobial Effects of Kordoi (Averrhoa carambola) Fruit Juice and
Bamboo (Bambusa polymorpha) Shoot Extract in Pork Nuggets. Food
Chem. 190, 41–49. doi:10.1016/j.foodchem.2015.05.070
Uuh-Narváez, J. J., González-Tamayo, M. A., and Segura-Campos, M. R. (2021). A
Study on Nutritional and Functional Study Properties of Mayan Plant Foods as
a New Proposal for Type 2 Diabetes Prevention. Food Chem. 341, 128247.
doi:10.1016/j.foodchem.2020.128247
Valim, F. d. P., Aguiar-Oliveira, E., Kamimura, E. S., Alves, V. D., and Maldonado,
R. R. (2016). Production of Star Fruit Alcoholic Fermented Beverage. Indian
J. Microbiol. 56 (4), 476–481. doi:10.1007/s12088-016-0601-9
Varela-Martínez, D. A., González-Curbelo, M. Á., González-Sálamo, J., and
Hernández-Borges, J. (2019). High-Throughput Analysis of Pesticides in
Minor Tropical Fruits from Colombia. Food Chem. 280, 221–230.
doi:10.1016/j.foodchem.2018.12.045
Vasant, R. A., and Narasimhacharya, A. V. R. L. (2014). Antidotal Activity of
Averrhoa carambola (Star Fruit) on Fluoride Induced Toxicity in Rats.
Interdiscip. Toxicol. 7 (2), 103–110. doi:10.2478/intox-2014-0014
Vasconcelos, C. M. L., Araújo, M. S., and Conde-Garcia, E. A. (2006).
Electrophysiological Effects of the Aqueous Extract of Averrhoa carambola
L. Leaves on the Guinea Pig Heart. Phytomedicine 13 (7), 501–508. doi:10.1016/
j.phymed.2005.01.013
Wakte, S. R., and Patil, D. A. (2011). Antimicrobial and Antioxidant Activity of
Averrhoa Carambola L. Fruit at Various Stages of Ripening. J. Herb. Med.
Toxicol. 5 (2), 121–129.
Wang, Y., Liu, M., Liu, L., Xia, J.-H., Du, Y.-G., and Sun, J.-S. (2018). The Structural
Revision and Total Synthesis of Carambolaflavone A. J. Org. Chem. 83 (7),
4111–4118. doi:10.1021/acs.joc.8b00008
Wei, S.-D., Chen, H., Yan, T., Lin, Y.-M., and Zhou, H.-C. (2014). Identification of
Antioxidant Components and Fatty Acid Profiles of the Leaves and Fruits from
Averrhoa carambola. LWT - Food Sci. Technol. 55, 278–285. doi:10.1016/j.lwt.2013.08.013
Wei, X. J., Xu, X. H., Chen, Z. F., Liang, T., Wen, Q. W., Qin, N., et al. (2018).
Protective Effects of 2-Dodecyl-6-Methoxycyclohexa-2,5-Diene-1,4-Dione
Isolated from Averrhoa carambola L. (Oxalidaceae) Roots on Neuron
Apoptosis and Memory Deficits in Alzheimer’s Disease. Cell. Physiol.
Biochem. 49 (3), 1064–1073. doi:10.1159/000493289
25 August 2021 | Volume 12 | Article 699899
Luan et al.
Wen, Q., Lin, X., Liu, Y., Xu, X., Liang, T., Zheng, N., et al. (2012). Phenolic and
Lignan Glycosides from the Butanol Extract of Averrhoa carambola L. Root.
Molecules 17, 12330–12340. doi:10.3390/molecules171012330
Wen, Q. W., Chen, C. X., Liang, X. M., Xu, X. H., and Huang, R. B. (2014). Isolation,
Identification and Determination for Benzoquinone Compounds from Averrhoa
carambola Root. Chin. J. Exp. Tradit. Med. Formulae 20 (11), 70–73.
doi:10.13422/j.cnki.syfjx.2014110070
Wen, Q. W., Liang, T., Qin, F. Z., Wei, J. B., He, Q. L., Luo, X., et al. (2013). Lyoniresinol 3α-
O-β-D-Glucopyranoside-Mediated Hypoglycaemia and its Influence on Apoptosis-
Regulatory Protein Expression in the Injured Kidneys of Streptozotocin-Induced Mice.
PLoS One 8 (12), e81772. doi:10.1371/journal.pone.0081772
Wijayaratne, D. R., Bavanthan, V., de Silva, M. V. C., Nazar, A. L. M., and
Wijewickrama, E. S. (2018). Star Fruit Nephrotoxicity: a Case Series and
Literature Review. BMC Nephrol. 19 (1), 288. doi:10.1186/s12882-018-1084-1
World Health Organization and Regional Office for the Western Pacific (2007).
WHO International Standard Terminologies on Traditional Medicine in the
Western Pacific Region. Manila: WHO Regional Office for the Western Pacific.
Wu, S. S., Sun, W., Xu, Z. C., Zhai, J. W., Li, X. P., Li, C. R., et al. (2020b). The
Genome Sequence of Star Fruit (Averrhoa carambola). Hortic. Res. 7, 95.
doi:10.1038/s41438-020-0307-3
Wu, X. C., Lu, S. Y., Zhou, X., Qin, L. H., Jiang, L. H., Li, Y. C., et al. (2020a). Anti-
hepatocarcinoma Effect of and its Mechanism of 2-Dodecyl-6-
Methoxycyclohexa-2,5-Diene-1,4-Dione in Averrhoa carambola L. Roots.
Chin. J. Hosp. Pharm. 40 (1), 42–47. doi:10.13286/j.1001-5213.2020.01.05
Xie, Q., Zhang, S., Chen, C., Li, J., Wei, X., Xu, X., et al. (2016). Protective Effect of
2-Dodecyl-6-Methoxycyclohexa-2, 5-Diene-1, 4-Dione, Isolated from
Averrhoa carambola L., Against Palmitic Acid-Induced Inflammation and
Apoptosis in Min6 Cells by Inhibiting the TLR4-MyD88-NF-κB Signaling
Pathway. Cell. Physiol. Biochem. 39 (5), 1705–1715. doi:10.1159/000447871
Xu, X. H., Phama, H. T. T., Wei, X. J., Qin, N., and Huang, R. B. (2017). Study of the
Extract of Averrhoa carambola L. Root on Renal Function in Diabetic Mice and
its Anti-Oxidative Action. Chin. Pharmacol. Bull. 33 (1), 95–100. doi:10.3969/
j.issn.1001-1978.2017.01.017
Xu, X., Liang, T., Lin, X., Wen, Q., Liang, X., Li, W., et al. (2015). Effect of the Total
Extract of Averrhoacarambola (Oxalidaceae) Root on the Expression Levels of
TLR4 and NF-κB in Streptozotocin-Induced Diabetic Mice. Cell. Physiol.
Biochem. 36 (6), 2307–2316. doi:10.1159/000430194
Xu, X., Liang, T., Wen, Q., Lin, X., Tang, J., Zuo, Q., et al. (2014). Protective Effects
of Total Extracts of Averrhoa carambola L. (Oxalidaceae) Roots on
Streptozotocin-Induced Diabetic Mice. Cell. Physiol. Biochem. 33 (5),
1272–1282. doi:10.1159/000358695
Yang, D.-P., Liu, X., Teng, C. P., Owh, C., Win, K. Y., Lin, M., et al. (2017).
Unexpected Formation of Gold Nanoflowers by a Green Synthesis Method as
Agents for a Safe and Effective Photothermal Therapy. Nanoscale 9 (41),
15753–15759. doi:10.1039/c7nr06286a
Yang, D., Jia, X., and Xie, H. (2019b). Heptyl Vicianoside and Methyl Caramboside
from Sour star Fruit. Nat. Product. Res. 33 (8), 1233–1236. doi:10.1080/
14786419.2018.1466123
Yang, D., Jia, X., Xie, H., and Wei, X. (2016). Further Dihydrochalcone
C-Glycosides from the Fruit of Averrhoa carambola. LWT - Food Sci.
Technol. 65, 604–609. doi:10.1016/j.lwt.2015.08.061
Yang, D., Xie, H., Jia, X., and Wei, X. (2015). Flavonoid C-Glycosides from Star
Fruit and Their Antioxidant Activity. J. Funct. Foods 16, 204–210. doi:10.1016/
j.jff.2015.04.048
Yang, D., Xie, H., Yang, B., and Wei, X. (2014). Two Tetrahydroisoquinoline
Alkaloids from the Fruit of Averrhoa carambola. Phytochem. Lett. 7, 217–220.
doi:10.1016/j.phytol.2013.12.007
Yang, L., Zhu, J., Song, L., Shi, X., Li, X., and Yu, R. (2012). Three Sesquiterpene
Compounds Biosynthesised from Artemisinic Acid Using Suspension-Cultured
Cells of Averrhoa carambola (Oxalidaceae). Nat. Product. Res. 26 (15),
1388–1394. doi:10.1080/14786419.2011.589055
Yang, Y., Jia, X., Xie, H., and Wei, X. (2020a). Dihydrochalcone C-Glycosides from
Averrhoa carambola Leaves. Phytochemistry 174, 112364. doi:10.1016/
j.phytochem.2020.112364
Yang, Y. X., Huang, T. M., Huang, R. B., and Xu, X. H. (2018). Study on the Liver
Tissue Anti-Oxidative Stress and Hypoglycemic Effects of Averrhoa carambola
Frontiers in Pharmacology | www.frontiersin.org
Phytochemistry and Pharmacology of Averrhoa carambola
Fruit Juice. Food Sci. Dev. 39 (9), 148–151. doi:10.3969/j.issn.1005-
6521.2018.09.028
Yang, Y. X., Huang, T. M., Huang, R. B., and Xu, X. H. (2019a). The Effects and
Mechanism of Averrhoa carambola Fruit Juice on Blood Glucose in Diabetic Mice.
J. Guangxi Med. Univ. 36 (1), 7–10. doi:10.16190/j.cnki.45-1211/r.2019.01.002
Yang, Y., Xie, H., Jiang, Y., and Wei, X. (2020b). Flavan-3-ols and 2-
Diglycosyloxybenzoates from the Leaves of Averrhoa carambola. Fitoterapia
140, 104442. doi:10.1016/j.fitote.2019.104442
Yao, Q., Gao, Y., Lai, C., Wu, C., Zhao, C. L., Wu, J. L., et al. (2020). The
Phytochemistry, Pharmacology and Applications of Melicope pteleifolia: A
Review. J. Ethnopharmacol. 251, 112546. doi:10.1016/j.jep.2020.112546
Yasawardene, P., Jayarajah, U., De Zoysa, I., and Seneviratne, S. L. (2020).
Mechanisms of Star Fruit (Averrhoa carambola) Toxicity: A Mini-Review.
Toxicon 187, 198–202. doi:10.1016/j.toxicon.2020.09.010
Yasawardene, P., Jayarajah, U., De Zoysa, I., and Seneviratne, S. L. (2021).
Nephrotoxicity and Neurotoxicity Following Star Fruit (Averrhoa
carambola) Ingestion: A Narrative Review. Trans. R. Soc. Trop. Med. Hyg.
doi:10.1093/trstmh/trab026
Zhang, H., Lu, S., Chen, L., Huang, X., Jiang, L., Li, Y., et al. (2020). 2-Dodecyl-6-
Methoxycyclohexa-2,5-Diene-1,4-Dione, Isolated from the Root of Averrhoa
carambola L., Protects against Diabetic Kidney Disease by Inhibiting TLR4/
TGFβ Signaling Pathway. Int. Immunopharmacol. 80, 106120. doi:10.1016/
j.intimp.2019.106120
Zhang, H., Wei, X., Lu, S., Lin, X., Huang, J., Chen, L., et al. (2019). Protective Effect of
DMDD, Isolated from the Root of Averrhoa carambola L., on High Glucose
Induced EMT in HK-2 Cells by Inhibiting the TLR4-BAMBI-Smad2/3 Signaling
Pathway. Biomed. Pharmacother. 113, 108705. doi:10.1016/j.biopha.2019.108705
Zheng, N., Lin, X., Wen, Q., Kintoko, S., Zhang, J., et al. (2013). Effect of 2-Dodecyl-
6-Methoxycyclohexa-2,5-Diene-1,4-Dione, Isolated from Averrhoa carambola
L. (Oxalidaceae) Roots, on Advanced Glycation End-Product-Mediated Renal
Injury in Type 2 Diabetic KKAy Mice. Toxicol. Lett. 219 (1), 77–84. doi:10.1016/
j.toxlet.2013.03.001
Zheng, N., Lin, X., Wen, Q., Kintoko, S., Zhang, J., et al. (2021). Effect of 2-Dodecyl-
6-Methoxycyclohexa-2, 5-Diene-1, 4-Dione, Isolated from Averrhoa carambola
L. (Oxalidaceae) Roots, on Advanced Glycation End-Product-Mediated Renal
Injury in Type 2 Diabetic KKAy Mice. Toxicol. Lett. 339, 88–96. doi:10.1016/
j.toxlet.2020.11.022
Zhou, X., Qin, L. H., Wu, X. C., Wu, Y. N., Chen, L. X., and Huang, R. B. (2019).
Inhibition Effect of 2-Dodecyl-6-Methoxycyclohexa-2,5-Diene-1,4-Dione on
Lung Cancer H1299 Cells. Chin. J. Clin. Pharmacol. 35 (21), 2675–2678.
Zhu, C., Xiao, Y., Liu, X., Han, J., Zhang, J., Wei, L., et al. (2015). Pioglitazone
Lowers Serum Retinol Binding Protein 4 by Suppressing its Expression in
Adipose Tissue of Obese Rats. Cell. Physiol. Biochem. 35 (2), 778–788.
doi:10.1159/000369737
Zulfajri, M., Dayalan, S., Li, W. Y., Chang, C. J., Chang, Y. P., and Huang, G. G.
(2019). Nitrogen-Doped Carbon Dots from Averrhoa carambola Fruit Extract
as a Fluorescent Probe for Methyl Orange. Sensors 19 (22), 5008. doi:10.3390/
s19225008
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26 August 2021 | Volume 12 | Article 699899
Luan et al. Phytochemistry and Pharmacology of Averrhoa carambola

GLOSSARY GSH reduced glutathione

GSH-Px glutathione peroxidase
ACP acid phosphatase HA hyaluronic acid
AI atherogenic index HDL-C high-density lipoprotein cholesterol
AIP atherogenic index of plasma Hyp hydroxyproline
AKP alkaline phosphatase iNOS inducible NO synthase
ALP alkaline phosphatase IL-6 interleukin-6
ALT alanine aminotransferase ISI insulin sensitivity index
AMPK α AMP-activated protein kinase α LDL-C low-density lipoprotein cholesterol
Ang II angiotensin II LN laminin
AST aspartate aminotransferase LPO lipid peroxidation
BAMBI BMP and activin membrane bound inhibitor MDA malondialdehyde
Bax bcl-associated X protein MPO myeloperoxidase
BUN blood urea nitrogen Myd88 myeloid differentiation factor 88
cAMP cyclic adenosine monophosphate NEFA non-esterified fatty acid
CAT catalase NF-κB nuclear factor-κB
C/EBPα CCAAT-enhancer binding protein α p-AMPK α phospho-AMPK α
Col III collagen type III PPAR-α/γ peroxisome proliferator activated receptors-α/γ
Col IV collagen type IV Scr serum creatinine
CTGF connective tissue growth factor SCD1 stearoyl-CoA desaturase 1
CVDs cardiovascular diseases SDH sorbitol dehydrogenase
CVF collagen volume fraction SGOT serum glutamate oxaloacetate transaminase
CysC cystatin C SGPT serum pyruvate transaminase
DENA diethylnitrosamine SOD superoxide dismutase
DMDD 2-dodecyl-6-methoxycyclohexa-2,5-diene- 1,4-dione SREBP-1c sterol regulatory element binding protein-1c
DPPH 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity STZ streptozotocin
eNOS endothelial NO synthase TAA total ascorbic acid
ECE endothelin-converting enzyme TC total cholesterol
ET-1 endothelin 1 TEAC trolox equivalent antioxidant capacity
FAS fatty acid synthase TG triglycerides
FBG fasting blood glucose TGF-β1 transforming growth factor beta 1
FFA free fatty acids TL total lipids
FINS fasting insulin TLR4 Toll-like receptors-4
FRAP ferric reducing antioxidant power tNOS total NO synthase
G-6-Pase glucose-6-phosphatase TNF-α tumor necrosis factor-α
GC-MS gas chromatography mass spectrometry TQ triglyceride
GHb glucosylated hemoglobin VLDL-C very low-density lipoprotein cholesterol

Frontiers in Pharmacology | www.frontiersin.org 27 August 2021 | Volume 12 | Article 699899